New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart

Abstract

The extracellular matrix (ECM), which contributes to structural homeostasis as well as to the regulation of cellular function, is enzymatically cleaved by proteases, such as matrix metalloproteinases and cathepsins, in the normal and diseased heart. During the past two decades, matricryptins have been defined as fragments of ECM with a biologically active cryptic site, namely the ‘matricryptic site,’ and their biological activities have been initially identified and clarified, including anti-angiogenic and anti-tumor effects. Thus, matricryptins are expected to be novel anti-tumor drugs, and thus widely investigated. Although there are a smaller number of studies on the expression and function of matricryptins in fields other than cancer research, some matricryptins have been recently clarified to have biological functions beyond an anti-angiogenic effect in heart. This review particularly focuses on the expression and function of basement membrane-derived matricryptins, including arresten, canstatin, tumstatin, endostatin and endorepellin, during cardiac diseases leading to heart failure such as cardiac hypertrophy and myocardial infarction.

1. INTRODUCTION

The extracellular matrix (ECM) surrounding cardiac cells acts as a structural framework for tissues and regulates the function of neighboring cells (e.g., cell adhesion, proliferation, migration and differentiation), and as such plays a key role in maintaining cellular homeostasis.^1,2) ECM is composed of collagens, fibronectin, laminin, proteoglycans (e.g., versican, perlecan, syndecan and glypican), matricellular proteins, a family of non-structural glycoproteins (e.g., secreted protein acidic and rich in cysteine, thrombospondins, tenascins and periostin), and glycosaminoglycans (e.g., chondroitin sulfate, heparan sulfate and hyaluronan).¹⁾ When a tissue is placed under a pathological condition, it is necessary for ECM to respond to the surrounding environment through binding a membrane receptor, integrin.^2,3) Thereafter, various etiological stimuli, such as oxidative stress, pressure overload, growth factors and inflammatory cytokines, promote the degradation of ECM by proteases including matrix metalloproteinases (MMPs) and cathepsins.^4,5) Matricryptin has been defined as a group of fragments cleaved from ECM which features matricryptic sites.⁶⁾ In a broad sense, the fragments of ECM-associated enzymes (MMPs, a disintegrin and metalloproteinases and lysyl oxidase) and ECM-affiliated proteins (e.g., mucins, galectins and semaphorins) are also considered as matricryptins.^7–9) Because most matricryptins have been clarified to be an endogenous anti-angiogenic and/or anti-tumor factor, they are expected to be novel anti-tumor drugs and are thus being widely investigated.¹⁰⁾ Matricryptins also regulate fibrosis, wound-healing, inflammation and vasocontractility, and are considered to be associated with various diseases, such as cancer, arthritis, pulmonary and kidney disease.^11–21) Over the past decade, the expression level of matricryptins has been revealed to change in patients with cardiovascular diseases and/or in experimental models of cardiovascular diseases (Table 1). Moreover, a novel type I collagen α1 chain-derived matricryptin, p1158/59, has been reported to facilitate left ventricular remodeling in post-myocardial infarction by regulating scar formation.²²⁾ Thus, the relevance of matricryptins to cardiac diseases has been gaining attention.

Table 1. Expression and Function of Basement Membrane-Derived Matricryptins in Heart

Matricryptins	Precursor protein	Expression and function	References
Arresten	Type IV collagen α1 chain	Increased expression in ischemia–reperfusion injury under mild hypothermic condition in pig	Lauten et al., 2016
Canstatin	Type IV collagen α2 chain	Decreased expression in mouse myocardial infarction model	Sugiyama et al., 2017
		Stimulation of proliferation, secretion of MMP-2 and MMP-9 and inhibition of contraction in myofibroblasts derived from rat myocardial infarction model	Sugiyama et al., 2017
		Inhibition of H2O2 apoptosis in H9c2 cardiomyoblasts	Kanazawa et al., 2017
		Stimulation of migration in rat cardiac fibroblasts	Okada et al., 2017
		Inhibition of isoproterenol-induced apoptosis in differentiated H9c2 cardiomyoblasts	Okada et al., 2016
Tumstatin	Type IV collagen α3 chain	Stimulation of proliferation and migration in rat cardiac fibroblasts	Yasuda et al., 2017b
		Inhibition of H2O2-induced apoptosis in H9c2 cardiomyoblasts	Yasuda et al., 2017a
		Decreased expression of ischemia–reperfusion injury under mild and deep hypothermic condition in pig	Lauten et al., 2016
		Increased expression of pressure-overload-induced hypertrophied myocardium in newborn rabbit	Nikolova et al., 2012
Endostatin	Type XVIII collagen α1 chain	Cardioprotective role on MCT-induced RV disease through inhibiting ICaT	Imoto et al., 2016
			Yasuda et al., 2015a
		Inhibition of bradykinin-induced mouse atrial contraction	Yasuda et al., 2015b
		Stimulation of proliferation and migration in rat cardiac fibroblasts	Okada et al., 2015
		Increased expression in pressure overload-induced mouse and newborn rabbit cardiac hypertrophy models	Givvimani et al., 2013, 2012, 2011, 2010
			Nikolova et al., 2012
		Increased expression in mouse myocardial infarction model	Qipshidze et al., 2012
		Protective role on rat myocardial infarction model	Isobe et al., 2010
		Increased expression in serum of pulmonary arterial hypertension, CHD and chronic heart failure patients	Damico et al., 2015
			Mitsuma et al., 2007
			Gouya et al., 2014
		Decreased expression in pericardial fluid of CAD patients with collaterals	Panchal et al., 2004
		No predictive information in CAD and CHD patients	Liou et al., 2006
			Eleuteri et al., 2016
			Ueland et al., 2015
Endorepellin	Perlecan domain V	Increased expression in ischemia–reperfusion injury under mild hypothermic condition in pig	Lauten et al., 2016

MMP: matrix metalloproteinase, MCT: monocrotaline, RV: right ventricular, I_CaT: T-type Ca²⁺ channel current, CHD: coronary heart disease, CAD: coronary artery disease.

The basement membrane communicates with adjacent cells to provide structural support, and serves as a storage site for soluble growth factors, which are then excised by proteases and endo-β-D-glucuronidase. It also mediates biological activities including migration, proliferation, adhesion and differentiation of marginal cells through interaction with integrins and other cell surface receptors.^23–25) In addition, the glomerular basement membrane is essential for filtration.²⁶⁾ The basement membrane is mainly composed of type IV collagen, laminin, entactin and perlecan. Moreover, types XV and XVIII collagens are also components of the basement membrane.²⁷⁾ Type IV collagen, which has six types of α chains (α1 to α6), is a major basement membrane component and consists of a triple helical structure.^28,29) The α1 and α2 chains are ubiquitously expressed in the basement membrane surrounding cardiomyocytes.^30,31) The non-collagenous (NC) 1 domain of type IV collagens has been identified to contain several matricryptins: arresten (α1), canstatin (α2), tumstatin (α3), tetrastatin (α4), pentastatin (α5) and hexastatin (α6).^32–35) The types XV and XVIII collagens, which belong to the multiplexin family, are proteoglycans found in the basement membrane.³⁶⁾ Restin is a fragment from the NC domain of type XV collagen.³⁷⁾ Endostatin is cleaved from type XVIII collagen by MMPs and other proteases.^38–44) Endorepellin is released from a domain V of perlecan, which is a large basement membrane-type heparan sulfate proteoglycan.^45,46) Recently, we and others have focused on some of these basement membrane-derived matricryptins, which are proposed to contribute to regulate cardiac remodeling through modulating cardiac cells (Table 1). In this review, we would like to introduce and summarize those studies, and discuss their roles in cardiac remodeling.

2. BASEMENT MEMBRANE-DERIVED MATRICRYPTINS

2.1. Arresten

Arresten, a 26 kDa fragment from the NC1 domain of the type IV collagen α1 chain, was first isolated from human placenta.³²⁾ Membrane type 1 (MT1)-MMP and MT2-MMP are thought to be involved in the release of arresten⁴⁷⁾ which is degraded by cathepsin S.⁴⁸⁾ Arresten exerts anti-angiogenic and subsequent anti-tumor activity by inhibiting proliferation, migration, tube formation and matrigel neovascularization, as well as promoting apoptosis in endothelial cells and by suppressing the migration and invasion of tumor cells.^32,49–51) These activities are mediated through binding α₁β₁ integrin,^32,49–51) and the C-terminus half of arresten is considered to be an active site.⁵⁰⁾ Arresten also suppresses the b-fibroblast growth factor-induced MMP-2 activation without suppressing its mRNA expression and secretion in mouse retinal endothelial cells.⁵²⁾ Nanoparticle-mediated arresten gene-delivery inhibits intimal hyperplasia in the murine vascular graft model.⁵³⁾ The expression level of arresten increased in ischemia–reperfusion injury under hypothermic conditions in female pigs.⁵⁴⁾ However, the biological activity of arresten in the heart has not yet been studied.

2.2. Canstatin

Canstatin, a 24 kDa peptide derived from the NC1 domain of the α2 chain of type IV collagen, was identified by Kamphaus et al.³³⁾ It is suggested that canstatin is released from the α2 chain by MT1-MMP and MT2-MMP, while arresten is released from the α1 chain.⁴⁷⁾ Canstatin inhibits angiogenesis and tumor growth through the inhibition of migration and tube formation in endothelial cells,^33,55) and through the induction of apoptosis in endothelial cells and cancer cells.^56–58) Both N-terminal (1–89 amino acid) fragments and C-terminal fragments (157–227 amino acid) of canstatin can inhibit in vivo tumor growth, mainly through the induction of apoptosis and the suppression of the proliferation in endothelial cells, respectively.^59,60) These anti-angiogenic and anti-tumor effects of canstatin are proposed to be mediated by binding its predicted receptor, α_vβ₃ and/or α_vβ₅ integrin.⁵⁶⁾ Although the expression level of canstatin in healthy individuals and patients with cardiac diseases has not yet been clarified, we recently clarified that canstatin is constitutively expressed in the normal myocardium, and that the expression level in the infarcted area is significantly decreased at 2 weeks after myocardial infarction in rats.⁶¹⁾ Because canstatin is degraded by cathepsin S,⁴⁸⁾ and the expression and activity of cathepsin S increases in the experimental mouse myocardial infarction model,⁶²⁾ canstatin might be degraded after myocardial infarction. Recently, we clarified that canstatin prevents isoproterenol-induced apoptosis through the inhibition of mitochondrial fission by suppressing the dephosphorylation of dynamin related protein 1 at Ser637 in differentiated H9c2 cardiomyoblasts.⁶³⁾ We also found in H9c2 cardiomyoblasts that canstatin suppressed hypoxia-induced apoptosis though the activation of the focal adhesion kinase (FAK)/Akt signaling pathway by binding α_vβ₃ and/or α_vβ₅ integrin.⁶⁴⁾ Furthermore, it has been shown that canstatin stimulates the migration of cardiac fibroblasts by the secretion of MMP-2,⁶⁵⁾ and that it promotes the proliferation and secretion of MMPs, as well as inhibits collagen gel contraction in myofibroblasts derived from the infarcted area of the myocardial infarction model rat.⁶¹⁾ Collectively, it is suggested that canstatin plays multiple roles in several types of cardiac cells, and potentially regulates cardiac remodeling.

2.3. Tumstatin

Tumstatin, a 28 kDa NC fragment cleaved from the C-terminal region of the type IV collagen α3 chain, was named by Maeshima et al. based on its unique property of causing “tumor stasis.”³⁵⁾ In adult humans, the type IV collagen α3 chain mRNA is highly expressed in the kidney, skeletal muscle and lung, but not in the heart, brain, placenta, liver or pancreas.⁶⁶⁾ Tumstatin is produced by MMPs, especially MMP-9.⁶⁷⁾ Its physiological concentration is approximately 336 ng/mL in normal mice⁶⁷⁾ and 68.5 ng/mL in the healthy human.¹⁵⁾ The serum concentration of tumstatin increases in human lung carcinoma patients with metastases (ca. 90.4 ng/mL), and conversely decreases in patients without metastases (ca. 45.2 ng/mL).¹⁵⁾ Tumstatin is well known to have both anti-angiogenetic and anti-tumor properties through the inhibition of proliferation and the induction of apoptosis in endothelial cells and tumor cells.^35,67–73) These effects of tumstatin are exerted through the regulation of the FAK/phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin pathway via binding its receptor, α_vβ₃ integrin, in an RGD (Arg-Gly-Asp)-independent manner.^{67,68,70–72,74,75)} Tumstatin also binds α₃β₁ integrin, which inhibits α_vβ₃ integrin activity.⁷⁶⁾ The fragment of 54–132 amino acids of tumstatin is important in its anti-angiogenic activity, and the cleaved fragments, such as T3 peptide (69–88 amino acids) and T7 peptide (74–98 amino acids), also preserve the activity.^71,77) It was reported that tumstatin suppresses vascular remodeling and inflammation in the experimental asthma model of mouse and sheep.^11,78) It also inhibits glomerular hypertrophy in experimental diabetic mice.⁷⁹⁾ The expression level of tumstatin was significantly increased in pressure-overload-induced hypertrophied myocardium in the newborn rabbit.⁸⁰⁾ On the other hand, the expression of tumstatin decreased in the myocardium after ischemia–reperfusion injury under mild and deep hypothermic conditions in pig.⁵⁴⁾ Recently, we have shown that the T3 peptide prevents H₂O₂-induced apoptosis in H9c2 cardiomyoblasts.⁸¹⁾ We also found that it stimulates the proliferation and migration of adult rat cardiac fibroblasts,⁸²⁾ indicating that tumstatin might participate in the process of cardiac remodeling during cardiac disease.

2.4. Endostatin

Endostatin, a C-terminal fragment of the collagen XVIII α1 chain localized in the vessel wall and basement membrane, was originally isolated from the conditioned media of a non-metastatic murine hemangioendothelioma cell line, EOMA, by O’Reilly et al.⁴²⁾ After the type XVIII collagen is enzymatically cleaved in the hinge region of the C-terminal NC 1 domain by proteinases, including MMPs (-2, -3, -7, -9, -12, -13 and -20), MT1-MMP, cathepsins (B, L, S and V) and elastase, then 20 and 24–30 kDa endostatin-containing peptides were released.^{38–41,43,44)} Endostatin is the most studied matricryptin, having potent anti-angiogenic properties and anti-tumor effects through the inhibition of neovascularization. The anti-angiogenic effect of endostatin has been clarified to be dependent on the inhibition of proliferation and migration, and the induction of autophagy and apoptosis in endothelial cells, while its molecular mechanisms are complex because endostatin is able to bind various cell surface receptors such as α_vβ₃, α_vβ₅, α₅β₁ integrins, vascular endothelial growth factor (VEGF) receptor (VEGFR) 1, VEGFR2, glypican-1 and glypican-4.^72,83–88) Furthermore, endostatin has a variety of cellular functions in addition to its anti-angiogenic and anti-tumor effects, such as the prevention of proliferation and migration of osteoblastoma through inhibition of the T-type calcium ion channel,⁸⁹⁾ the reduction of blood pressure via nitric oxide (NO) production,^19,90,91) the inhibition of dermal and pulmonary fibrosis,^20,92,93) and the prevention of inflammatory arthritis.^14,21,94,95) Based on these studies, endostatin-derived recombinant proteins are expected to be used as anti-tumor, anti-fibrotic and anti-rheumatoid arthritis drugs. Among these, a modified human endostatin with a zinc binding peptide in the N-terminus (ZBP-endostatin; its trade name is Endostar), which is more stable and effective than native endostatin, has been approved by the State Food and Drug Administration of China for the treatment of non-small-cell lung cancer.^96–98) Several studies have shown the upregulation of endostatin expression in heart tissue and/or serum level in a variety of cardiovascular diseases.^80,99–106) The median serum concentration of endostatin in healthy subjects ranges from 14–78 ng/mL.^107–109) A high serum level of endostatin seems be correlated with a higher risk of mortality in patients with pulmonary arterial hypertension (ca. 95 ng/mL) and chronic heart failure (ca. 245 ng/mL).^99,104) On the other hand, several studies suggest that the serum endostatin level adds no predictive information in patients with coronary artery disease and chronic heart failure.^110–112) Thus, it remains unclear whether the upregulation of endostatin in cardiac diseases plays a role in the progression of the cardiac disease. Givvimani et al. have reported that the transition from compensatory to decompensate heart failure is associated with the upregulation of endostatin following the activation of MMP-9 in the mouse aortic stenosis model.¹⁰³⁾ In the rabbit pressure overload-induced left ventricular hypertrophy model, the suppression of endostatin-release by an MMP-9 specific inhibitor-treatment preserved cardiac contractility.⁸⁰⁾ In patients with coronary arterial disease, high pericardial endostatin level is related to the decreases in coronary collateral formation, which is beneficial for diminishing the infarcted area and improving the prognosis of the patients.¹¹³⁾ These studies indicate that endostatin can be harmful in the pathology of cardiac disease. On the other hand, several studies have reported cardioprotective effects of endostatin. Isobe et al. reported that an anti-endostatin antibody treatment exacerbates the pathology of left ventricular myocardial infarction through the activation of MMP-2, -9 and collagen production.¹¹⁴⁾ The T-type calcium ion channel, which participates in the process of cardiac remodeling, including cardiac hypertrophy and arrhythmia, is re-expressed in the pressure overload-induced hypertrophied heart.^115–119) We have recently shown that endostatin inhibits the T-type calcium ion channel in a ventricular cardiomyocyte from guinea pig,¹²⁰⁾ as well as in a cardiomyocyte from hypertrophied right ventricles of monocrotaline-induced pulmonary hypertensive rats.¹²¹⁾ In addition, treatment with small interfering (si)RNA against collagen XVIII decreases the survival rate and exacerbates right ventricular remodeling.¹²¹⁾ Endostatin also has biological effects in the heart, such as the inhibition of bradykinin-induced atrial contractions, perhaps through inhibition of the L-type calcium channel¹²²⁾ and the stimulation of the proliferation and migration of cardiac fibroblasts through activation of the PI3K/Akt signaling pathway.¹²³⁾ Further study is required to clarify whether endostatin exacerbates or prevents cardiac remodeling.

2.5. Endorepellin

Perlecan, a large heparan sulfate proteoglycan, is ubiquitously expressed in the basement membrane.⁴⁵⁾ Endorepellin, a fragment of domain V of perlecan’s core protein (ca. 85 kDa), named by Mongiat et al.,⁴⁶⁾ has an anti-angiogenic function through mechanisms which include the inhibition of endothelial cell migration, tube formation and the induction of autophagy in endothelial cells.^{46,124–128)} These effects were mediated through antagonism to its dual receptors, α₂β₁ integrin and VEGFR2.^124–128) On the other hand, endorepellin exerts a pro-angiogenic effect on brain endothelial cells through VEGF production by binding the α₅β₁ integrin.¹²⁹⁾ Although the precise mechanism of endorepellin cleavage from perlecan has not been clarified, cathepsins, MMPs and chymase are thought to be candidate molecules responsible for its cleavage.¹³⁰⁾ Endorepellin is further cleaved into LG3 fragment, a C-terminus fragment cleaved by cathepsin L, and bone morphogenetic protein-1-Tolloid-like proteases,^131,132) which promotes neointima formation in the vascular rejection of allograft through the migration and survival of vascular smooth muscle cells via the extracellular signal-regulated kinase-dependent pathway.¹³³⁾ Both perlecan and endorepellin have key roles in the development of cardiovascular and musculoskeletal function in zebrafish embryos.¹³⁴⁾ Ischemia–reperfusion injury under mild hypothermic condition in female pig caused a significant increase in LG3 expression.⁵⁴⁾ Currently, there have been no further reports determining the precise roles of endorepellin in the mammalian heart tissue and cells.

3. PERSPECTIVES ON THE ROLES OF BASEMENT MEMBRANE-DERIVED MATRICRYPTINS IN CARDIAC DISEASES

In the development of cardiac diseases, matricryptins cleaved from the basement membrane are expected to exert various biological functions on cardiac cells, and to contribute to the regulation of pathological cardiac remodeling processes (Fig. 1).

Fig. 1. Basement Membrane-Derived Matricryptins in the Development of Cardiac Diseases

Pathological cardiac remodeling associated with myocardial infarction and cardiac hypertrophy, which are caused by ischemic stress and pressure overload, respectively, eventually results in decompensated heart failure. Matricryptins cleaved from the extracellular matrix (ECM) by proteases exert various biological functions on cardiac cells, and might regulate the pathological cardiac remodeling both positively and negatively. Endothelial angiogenesis mediates enhanced cardiomyocyte viability and adaptive hypertrophy. Matricryptins can inhibit endothelial angiogenesis. After myocardial infarction, cardiac fibroblasts migrate into the infarcted area, proliferate, secrete matrix metalloproteinases (MMPs) and differentiate into myofibroblasts. Myofibroblasts are involved in wound healing by the secretion of ECM proteins, and stabilize the scar tissue by contraction. On the other hand, chronic activation of fibroblasts/myofibroblasts induces excessive fibrosis. Matricryptins probably have a key role in these fibrotic processes through the regulation of fibroblast/myofibroblast functions. Ischemia-induced cell death and pressure overload-induced cardiomyocyte hypertrophy accompanied by functional and electrical remodeling cause contractile dysfunction and arrhythmia. Matricryptins might exert a cytoprotective effect partly through activating a survival pathway and modulating ion channel activity.

Following myocardial infarction, adequate angiogenesis is necessary for the survival and adaptive hypertrophy of the remaining cardiomyocytes to gain oxygen and nutrients.^135,136) Therefore, the induction of angiogenesis is expected to be one therapeutic method for myocardial infarction.^137,138) On the other hand, inadequate angiogenesis mediates the transition from compensated cardiac hypertrophy to decompensated heart failure.¹³⁶⁾ All of the basement membrane-derived matricryptins focused on in this article have an anti-angiogenic effect. The disruption of angiogenesis by arresten and endorepellin increased in the injured myocardium after ischemia–reperfusion,⁵⁴⁾ which might exacerbate the pathological condition. It is also presumed that the decreases in canstatin in the area of myocardial infarction,⁶¹⁾ and in tumstatin in the endothelial basement membrane of the injured myocardium after ischemia–reperfusion⁵⁴⁾ potentially promote adaptive cardiac remodeling through the promotion of angiogenesis. Conversely, increases in tumstatin in the pressure-overload-induced hypertrophied myocardium⁸⁰⁾ might contribute to pathological cardiac hypertrophy. The endostatin level in pericardial fluid is decreased in patients with coronary artery disease with collateral formation, in comparison to those without it.¹¹³⁾ Exogenous hydrogen sulfide inhibits endostatin expression and exerts a cardioprotective effect in the mouse myocardial infarction model.¹⁰⁶⁾ These observations indirectly suggest that endostatin is detrimental in cardiac remodeling by its anti-angiogenic effect. However, anti-endostatin antibody-treatment leads to a deterioration in mortality, cardiac hypertrophy and myocardial fibrosis in the rat myocardial infarction model, despite promoting angiogenesis.¹¹⁴⁾ Moreover, knockdown of the endostatin gene worsens monocrotaline-induced right ventricular remodeling.¹²¹⁾ Thus, increased endostatin during myocardial infarction and pressure overload-induced hypertrophy potentially exerts a cardioprotective effect through the suppression of pathological cardiac remodeling, regardless of its anti-angiogenic effect.

After myocardial infarction, cardiac fibroblasts migrate into the infarcted area, proliferate and differentiate into myofibroblasts, which are involved in wound healing by the secretion of collagens and the maturation of scar tissue through contraction. On the other hand, chronic activation of myofibroblasts induces excessive fibrosis, which causes cardiac dysfunction.^139,140) We have clarified that canstatin promotes the migration of cardiac fibroblasts,⁶⁵⁾ stimulates the proliferation and secretion of MMPs, and inhibits collagen gel contraction in myofibroblasts isolated from the area of myocardial infarction.⁶¹⁾ In addition, the expression of canstatin in the infarcted area is significantly decreased at 2 weeks after myocardial infarction in rats.⁶¹⁾ In the acute phase of myocardial infarction, canstatin likely induces the migration of cardiac fibroblasts into the infarcted area. In the late phase, decreased canstatin in the area of myocardial infarction leads to the suppression of proliferation and ECM degradation through the inhibition of MMPs secretion, as well as the promotion of contraction in myofibroblasts, which latently contribute to the maturation of scar tissue. Tumstatin is significantly increased in the pressure-overload-induced hypertrophied myocardium during both compensated and decompensated stages.⁸⁰⁾ We have shown that tumstatin stimulates the proliferation and migration of cardiac fibroblasts.⁸²⁾ Thus, tumstatin might play a pro-fibrotic role in the development of decompensated cardiac hypertrophy. It was demonstrated that an anti-endostatin antibody increased fibrosis in the non-infarcted area of the myocardial infarction model rat.¹¹⁴⁾ In addition, an endostatin-derived peptide, E4, prevented bleomycin-induced pulmonary fibrosis.^20,92) In contrast, we have shown the pro-fibrotic effects of endostatin, including the stimulation of proliferation, migration and wound healing in cardiac fibroblasts.¹²³⁾ Although endostatin is assumed to play a key role in myocardial fibrotic responses through the regulation of fibroblast functions, further study is needed to clarify whether it worsens or suppresses myocardial fibrosis.

Since cardiomyocytes have poor regenerative capacity, ischemia (hypoxia)-induced cardiomyocyte death associated with myocardial infarction results in contractile dysfunction and subsequent decompensated heart failure.^141,142) Pressure overload causes electrical remodeling, which is associated with cardiac hypertrophy, contractile disorder and arrhythmia through the functional alteration of ion channels, such as transient receptor potential channels, voltage-dependent calcium channels, voltage-gated sodium channels, inositol 1,4,5-trisphosphate receptor and potassium channels, in cardiomyocytes.^{115,143–151)} Most matricryptins exhibit a pro-apoptotic effect on endothelial cells. On the other hand, canstatin exerts a cytoprotective effects against cell death-inducing stress.^63,64) An active fragment of tumstatin, the T3 peptide, also prevents oxidative stress-induced apoptosis⁸¹⁾ in H9c2 cardiomyoblasts. From experiments using a neutralizing antibody,¹¹⁴⁾ endostatin is supposed to have a cardioprotective effect. Cav3.2, a T-type calcium channel, plays an important role in the pathogenesis of cardiac hypertrophy via the activation of the calcineurin/nuclear factor of activated T cells pathways.¹¹⁵⁾ Pharmacological inhibition of the T-type calcium channel reduces arrhythmia in a mouse model of dilated cardiomyopathy, and reduces sudden death in the mouse myocardial infarction model.¹¹⁷⁾ It was previously reported that endostatin prevented the proliferation and migration of osteoblastoma through the inhibition of T-type calcium channel.⁸⁹⁾ We have shown that endostatin inhibits the T-type calcium channel expressed in a ventricular cardiomyocyte from guinea pig, and in a hypertrophied cardiomyocyte from the right ventricle of monocrotaline-induced pulmonary hypertensive rat.^120,121) We also showed that a knockdown of the collagen XVIII (endostatin) gene by siRNA-treatment decreases the survival rate and exacerbates the monocrotaline-induced right ventricular remodeling.¹²¹⁾ Thus, the cardioprotective effect of endostatin might be exerted through the inhibition of T-type calcium channel activity. Collectively, it is conceivable that basement membrane-derived matricryptins are likely endogenous cardioprotective peptides.

4. POSSIBILE APPLICATION OF BASEMENT MEMBRANE-DERIVED MATRICRYPTINS TO THE TREATMENT OF CARDIAC DISEASES

Finally, we discuss the possibility of basement membrane-derived matricryptins as a novel therapeutic target for cardiac diseases. While the N-terminal fragment of canstatin inhibits angiogenesis, mainly through the induction of endothelial apoptosis, the anti-angiogenic activity of the C-terminal fragment occurs specifically through the inhibition of endothelial proliferation.^59,60) The N-terminal fragment of endostatin has both anti-angiogenic and anti-tumor effects.¹⁵²⁾ On the other hand, the C-terminal fragment of endostatin, named E4, exerts an anti-fibrotic effect.²⁰⁾ While the LG1/2 region of endorepellin causes autophagy in endothelial cells via VEGFR2 downregulation, LG3 does not have such a function.¹²⁷⁾ Thus, there might be various active sites which exert different physiological effects in each matricryptin. However, the specific regions which exert cardioprotective and/or pro/anti-fibrotic effects have not yet been clarified. Therefore, it is necessary to elucidate the specific active sites, and to produce applicable short fragments of matricryptins with higher efficacy in order to apply these fragments to the treatment of specific cardiac diseases.

Endostatin has a very short half-life of within 1–2 h. Fc-endostatin, a recombinant human endostatin conjugated to the Fc domain of immunoglobulin G, prolongs the half-life to more than one week, which allows it to exert its anti-tumor activity at a lower concentration than the intact endostatin.¹⁵³⁾ The terminal elimination half-life of endostar-loaded polyethylene glycol-modified poly DL-lactide-co-glycolide nanoparticles is more than one day, and the anti-tumor effect of endostar-loaded nanoparticles is stronger than endostar-alone.¹⁵⁴⁾ Thus, the adjustment of their pharmacokinetic behavior is also thought to be necessary for the clinical application of matricryptins.

An anti-VEGF monoclonal antibody, bevacizumab, which is used as an anti-tumor drug, increases the risk of hypertension.¹⁵⁵⁾ Fc-conjugated endostatin, which has anti-angiogenic and anti-tumor effects, also lowers blood pressure through NO production, and counteracts the elevated blood pressure induced by an anti-VEGF antibody-treatment in mice.⁹¹⁾ Thus, there might be an advantage in combination treatment using endostatin and anti-VEGF antibody for anti-tumor therapy. On the other hand, the potential interaction between drugs traditionally used to treat heart failure and basement membrane-derived matricryptins has not been clarified. β-Adrenergic receptor antagonists, such as carvedilol, bisoprolol and metoprolol, are widely used as therapeutic agents for heart failure.¹⁵⁶⁾ Stimulation of the β-adrenergic receptor causes cardiomyocyte apoptosis, which is suppressed by ECM through binding β₁ integrin and activating the FAK/PI3K/Akt pathway.¹⁵⁷⁾ Thus, matricryptins such as arresten, tumstatin, endostatin and endorepellin, which can bind β₁ integrin, might mediate the cardioprotective effect of β-adrenergic receptor antagonists.

Inhibition of the renin–angiotensin–aldosterone system by angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers (ARBs) is widely used in the treatment of cardiovascular diseases.¹⁵⁸⁾ Various ACE inhibitory peptides derived from animals and plants have been found.¹⁵⁹⁾ An amino acid sequence of the NC1 domain of type XVIII collagen in the vicinity of endostatin resembles the snake venom-derived bradykinin-potentiating peptides, which strongly inhibit ACE activity.¹⁶⁰⁾ Isobe et al. reported that an anti-endostatin antibody increased ACE activity in the infarcted myocardium.¹¹⁴⁾ Thus, it is presumed that an XVIII-type collagen fragment which includes endostatin may act as an endogenous ACE inhibitor. Both AT1R and β₁ integrin act as mechanosensors for pressure-overload in cardiomyocytes, and are involved in myocardial hypertrophy and contraction via activation of the mitogen-activated protein kinase pathway, FAK, Akt and integrin-linked kinase (ILK).¹⁶¹⁾ Angiotensin II can activate ILK, a serine/threonine kinase, which binds the C-terminus of β₁ integrin, and is associated with cardiomyocyte hypertrophy.¹⁶²⁾ Therefore, β₁ integrin-binding matricryptins may mediate the therapeutic effect of ARBs via modulating the mechanical stress-induced signaling pathway in pressure overload-induced cardiac hypertrophy.

5. CONCLUSION

Many kinds of matricryptins have been identified during the past two decades. The functional analysis of matricryptins has been performed, and almost all of them have been clarified to exhibit anti-angiogenic and anti-tumor effects. Based on this experimental groundwork, the application of matricryptins-derived proteins as an anti-tumor, anti-arthritis and anti-fibrotic drug is expected. Actually ZBP-endostatin has already been approved in China. On the other hand, during the past decade, several studies have demonstrated that expression level of basement membrane-derived matricryptins changes in cardiac disease patients and/or in experimental models of cardiac diseases. In particular, we and several other groups have recently proposed that matricryptins exhibit various biological functions on cardiac cells, and contribute to regulate cardiac remodeling. These findings indicate that the matricryptins function as endogenous regulatory factors in cardiac remodeling, and are thus potential targets for the development of novel drugs against heart failure. However, there are still many unsolved points in the role of matricryptins in the normal and diseased heart. The blood concentration of endostatin in patients with cardiac diseases has been well documented, while little is known about the concentration of other basement membrane-derived matricryptins. For this reason, further studies are needed on basement membrane-derived matricryptins other than endostatin. Their elucidation is important to future therapeutic pathways in the treatment of cardiac diseases. It is expected that further research in this field will progress in the near future.

Conflict of Interest

The authors declare no conflict of interest.

REFERENCES

• 1) Rienks M, Papageorgiou AP, Frangogiannis NG, Heymans S. Myocardial extracellular matrix: an ever-changing and diverse entity. Circ. Res., 114, 872–888 (2014).
• 2) Valiente-Alandi I, Schafer AE, Blaxall BC. Extracellular matrix-mediated cellular communication in the heart. J. Mol. Cell. Cardiol., 91, 228–237 (2016).
• 3) Chen C, Li R, Ross RS, Manso AM. Integrins and integrin-related proteins in cardiac fibrosis. J. Mol. Cell. Cardiol., 93, 162–174 (2016).
• 4) Müller AL, Dhalla NS. Role of various proteases in cardiac remodeling and progression of heart failure. Heart Fail. Rev., 17, 395–409 (2012).
• 5) Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev., 87, 1285–1342 (2007).
• 6) Davis GE, Bayless KJ, Davis MJ, Meininger GA. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol., 156, 1489–1498 (2000).
• 7) Ricard-Blum S, Salza R. Matricryptins and matrikines: biologically active fragments of the extracellular matrix. Exp. Dermatol., 23, 457–463 (2014).
• 8) Ricard-Blum S, Vallet SD. Proteases decode the extracellular matrix cryptome. Biochimie, 122, 300–313 (2016).
• 9) Ricard-Blum S, Vallet SD. Matricryptins network with matricellular receptors at the surface of endothelial and tumor cells. Front. Pharmacol., 7, 11 (2016).
• 10) Monboisse JC, Oudart JB, Ramont L, Brassart-Pasco S, Maquart FX. Matrikines from basement membrane collagens: a new anti-cancer strategy. Biochim. Biophys. Acta, 1840, 2589–2598 (2014).
• 11) Burgess JK, Boustany S, Moir LM, Weckmann M, Lau JY, Grafton K, Baraket M, Hansbro PM, Hansbro NG, Foster PS, Black JL, Oliver BG. Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness. Am. J. Respir. Crit. Care Med., 181, 106–115 (2010).
• 12) Carlsson AC, Ostgren CJ, Lanne T, Larsson A, Nystrom FH, Arnlov J. The association between endostatin and kidney disease and mortality in patients with type 2 diabetes. Diabetes Metab., 42, 351–357 (2016).
• 13) Gruszka A, Kunert-Radek J, Pawlikowski M, Stepien H. Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with pituitary adenomas. Pituitary, 8, 163–168 (2005).
• 14) Kurosaka D, Yoshida K, Yasuda J, Yokoyama T, Kingetsu I, Yamaguchi N, Joh K, Matsushima M, Saito S, Yamada A. Inhibition of arthritis by systemic administration of endostatin in passive murine collagen induced arthritis. Ann. Rheum. Dis., 62, 677–679 (2003).
• 15) Luo YQ, Yao LJ, Zhao L, Sun AY, Dong H, Du JP, Wu SZ, Hu W. Development of an ELISA for quantification of tumstatin in serum samples and tissue extracts of patients with lung carcinoma. Clin. Chim. Acta, 411, 510–515 (2010).
• 16) Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing. Matrix Biol., 27, 535–546 (2008).
• 17) Sumi M, Satoh H, Kagohashi K, Ishikawa H, Sekizawa K. Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosis. J. Clin. Lab. Anal., 19, 146–149 (2005).
• 18) Suzuki M, Iizasa T, Ko E, Baba M, Saitoh Y, Shibuya K, Sekine Y, Yoshida S, Hiroshima K, Fujisawa T. Serum endostatin correlates with progression and prognosis of non-small cell lung cancer. Lung Cancer, 35, 29–34 (2002).
• 19) Wenzel D, Schmidt A, Reimann K, Hescheler J, Pfitzer G, Bloch W, Fleischmann BK. Endostatin, the proteolytic fragment of collagen XVIII, induces vasorelaxation. Circ. Res., 98, 1203–1211 (2006).
• 20) Yamaguchi Y, Takihara T, Chambers RA, Veraldi KL, Larregina AT, Feghali-Bostwick CA. A peptide derived from endostatin ameliorates organ fibrosis. Sci. Transl. Med., 4, 136ra71 (2012).
• 21) Yue L, Wang H, Liu LH, Shen YX, Wei W. Anti-adjuvant arthritis of recombinant human endostatin in rats via inhibition of angiogenesis and proinflammatory factors. Acta Pharmacol. Sin., 25, 1182–1185 (2004).
• 22) Lindsey ML, Iyer RP, Zamilpa R, Yabluchanskiy A, DeLeon-Pennell KY, Hall ME, Kaplan A, Zouein FA, Bratton D, Flynn ER, Cannon PL, Tian Y, Jin YF, Lange RA, Tokmina-Roszyk D, Fields GB, de Castro Bras LE. A novel collagen matricryptin reduces left ventricular dilation post-myocardial infarction by promoting scar formation and angiogenesis. J. Am. Coll. Cardiol., 66, 1364–1374 (2015).
• 23) Hynes RO. The extracellular matrix: not just pretty fibrils. Science, 326, 1216–1219 (2009).
• 24) Kruegel J, Miosge N. Basement membrane components are key players in specialized extracellular matrices. Cell. Mol. Life Sci., 67, 2879–2895 (2010).
• 25) Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J. Biol. Chem., 271, 10079–10086 (1996).
• 26) Suh JH, Miner JH. The glomerular basement membrane as a barrier to albumin. Nat. Rev. Nephrol., 9, 470–477 (2013).
• 27) Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer, 3, 422–433 (2003).
• 28) Hudson BG, Reeders ST, Tryggvason K. Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. J. Biol. Chem., 268, 26033–26036 (1993).
• 29) Kühn K. Basement membrane (type IV) collagen. Matrix Biol., 14, 439–445 (1995).
• 30) Watanabe T, Kusachi S, Yamanishi A, Kumashiro H, Nunoyama H, Sano I, Nakahama M, Murakami T, Naito I, Ninomiya Y, Tsuji T. Localization of type IV collagen alpha chain in the myocardium of dilated and hypertrophic cardiomyopathy. Jpn. Heart J., 39, 753–762 (1998).
• 31) Yamanishi A, Kusachi S, Nakahama M, Ninomiya Y, Watanabe T, Kumashiro H, Nunoyama H, Kondo J, Naito I, Tsuji T. Sequential changes in the localization of the type IV collagen alpha chain in the infarct zone: immunohistochemical study of experimental myocardial infarction in the rat. Pathol. Res. Pract., 194, 413–422 (1998).
• 32) Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R. Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res., 60, 2520–2526 (2000).
• 33) Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J. Biol. Chem., 275, 1209–1215 (2000).
• 34) Karagiannis ED, Popel AS. Identification of novel short peptides derived from the alpha 4, alpha 5, and alpha 6 fibrils of type IV collagen with anti-angiogenic properties. Biochem. Biophys. Res. Commun., 354, 434–439 (2007).
• 35) Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grunkemeyer JA, Ericksen MB, Hopfer H, Xiao Y, Stillman IE, Kalluri R. Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J. Biol. Chem., 275, 21340–21348 (2000).
• 36) Ortega N, Werb Z. New functional roles for non-collagenous domains of basement membrane collagens. J. Cell Sci., 115, 4201–4214 (2002).
• 37) Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knebelmann B, Sukhatme VP. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun., 255, 735–739 (1999).
• 38) Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J., 19, 1187–1194 (2000).
• 39) Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaisse J. Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett., 486, 247–251 (2000).
• 40) Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkila P, Rehn M, Sorsa T, Salo T, Pihlajaniemi T. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp. Cell Res., 307, 292–304 (2005).
• 41) Ma DH, Yao JY, Kuo MT, See LC, Lin KY, Chen SC, Chen JK, Chao AS, Wang SF, Lin KK. Generation of endostatin by matrix metalloproteinase and cathepsin from human limbocorneal epithelial cells cultivated on amniotic membrane. Invest. Ophthalmol. Vis. Sci., 48, 644–651 (2007).
• 42) O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277–285 (1997).
• 43) Veillard F, Saidi A, Burden RE, Scott CJ, Gillet L, Lecaille F, Lalmanach G. Cysteine cathepsins S and L modulate anti-angiogenic activities of human endostatin. J. Biol. Chem., 286, 37158–37167 (2011).
• 44) Wen W, Moses MA, Wiederschain D, Arbiser JL, Folkman J. The generation of endostatin is mediated by elastase. Cancer Res., 59, 6052–6056 (1999).
• 45) Gubbiotti MA, Neill T, Iozzo RV. A current view of perlecan in physiology and pathology: a mosaic of functions. Matrix Biol., 57–58, 285–298 (2017).
• 46) Mongiat M, Sweeney SM, San Antonio JD, Fu J, Iozzo RV. Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J. Biol. Chem., 278, 4238–4249 (2003).
• 47) Rebustini IT, Myers C, Lassiter KS, Surmak A, Szabova L, Holmbeck K, Pedchenko V, Hudson BG, Hoffman MP. MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis. Dev. Cell, 17, 482–493 (2009).
• 48) Wang B, Sun J, Kitamoto S, Yang M, Grubb A, Chapman HA, Kalluri R, Shi GP. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J. Biol. Chem., 281, 6020–6029 (2006).
• 49) Aikio M, Alahuhta I, Nurmenniemi S, Suojanen J, Palovuori R, Teppo S, Sorsa T, Lopez-Otin C, Pihlajaniemi T, Salo T, Heljasvaara R, Nyberg P. Arresten, a collagen-derived angiogenesis inhibitor, suppresses invasion of squamous cell carcinoma. PLOS ONE, 7, e51044 (2012).
• 50) Nyberg P, Xie L, Sugimoto H, Colorado P, Sund M, Holthaus K, Sudhakar A, Salo T, Kalluri R. Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor. Exp. Cell Res., 314, 3292–3305 (2008).
• 51) Sudhakar A, Nyberg P, Keshamouni VG, Mannam AP, Li J, Sugimoto H, Cosgrove D, Kalluri R. Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin. J. Clin. Invest., 115, 2801–2810 (2005).
• 52) Boosani CS, Nalabothula N, Sheibani N, Sudhakar A. Inhibitory effects of arresten on bFGF-induced proliferation, migration, and matrix metalloproteinase-2 activation in mouse retinal endothelial cells. Curr. Eye Res., 35, 45–55 (2010).
• 53) Wang RF, Meng QY. Nanoparticle-mediated arresten gene inhibits neointimal formation of vein grafts: an experimental research. J. Thorac. Dis., 8, 3081–3086 (2016).
• 54) Lauten A, Gerhard-Garcia A, Suhr F, Fischer JH, Figulla HR, Bloch W. Impact of ischemia–reperfusion on extracellular matrix processing and structure of the basement membrane of the heart. PLOS ONE, 9, e92833 (2014).
• 55) Hou WH, Wang TY, Yuan BM, Chai YR, Jia YL, Tian F, Wang JM, Xue LX. Recombinant mouse canstatin inhibits chicken embryo chorioallantoic membrane angiogenesis and endothelial cell proliferation. Acta Biochim. Biophys. Sin. (Shanghai), 36, 845–850 (2004).
• 56) Magnon C, Galaup A, Mullan B, Rouffiac V, Bidart JM, Griscelli F, Opolon P, Perricaudet M. Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with alphavbeta3 and alphavbeta5 integrins. Cancer Res., 65, 4353–4361 (2005).
• 57) Panka DJ, Mier JW. Canstatin inhibits Akt activation and induces Fas-dependent apoptosis in endothelial cells. J. Biol. Chem., 278, 37632–37636 (2003).
• 58) Xing YN, Deng P, Xu HM. Canstatin induces apoptosis in gastric cancer xenograft growth in mice through the mitochondrial apoptotic pathway. Biosci. Rep., 34, 189–194 (2014).
• 59) He GA, Luo JX, Zhang TY, Hu ZS, Wang FY. The C-terminal domain of canstatin suppresses in vivo tumor growth associated with proliferation of endothelial cells. Biochem. Biophys. Res. Commun., 318, 354–360 (2004).
• 60) He GA, Luo JX, Zhang TY, Wang FY, Li RF. Canstatin-N fragment inhibits in vitro endothelial cell proliferation and suppresses in vivo tumor growth. Biochem. Biophys. Res. Commun., 312, 801–805 (2003).
• 61) Sugiyama A, Okada M, Yamawaki H. Pathophysiological roles of canstatin on myofibroblasts after myocardial infarction in rats. Eur. J. Pharmacol., 807, 32–43 (2017).
• 62) Chen H, Wang J, Xiang MX, Lin Y, He A, Jin CN, Guan J, Sukhova GK, Libby P, Wang JA, Shi GP. Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction. Cardiovasc. Res., 100, 84–94 (2013).
• 63) Okada M, Morioka S, Kanazawa H, Yamawaki H. Canstatin inhibits isoproterenol-induced apoptosis through preserving mitochondrial morphology in differentiated H9c2 cardiomyoblasts. Apoptosis, 21, 887–895 (2016).
• 64) Kanazawa H, Imoto K, Okada M, Yamawaki H. Canstatin inhibits hypoxia-induced apoptosis through activation of integrin/focal adhesion kinase/Akt signaling pathway in H9c2 cardiomyoblasts. PLOS ONE, 12, e0173051 (2017).
• 65) Okada M, Murata N, Yamawaki H. Canstatin stimulates migration of rat cardiac fibroblasts via secretion of matrix metalloproteinase-2. Am. J. Physiol. Cell Physiol., 312, C199–C208 (2017).
• 66) Mariyama M, Leinonen A, Mochizuki T, Tryggvason K, Reeders ST. Complete primary structure of the human alpha 3(IV) collagen chain. Coexpression of the alpha 3(IV) and alpha 4(IV) collagen chains in human tissues. J. Biol. Chem., 269, 23013–23017 (1994).
• 67) Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, Sudhakar A, Kalluri R. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alpha(v)beta(3) integrin. Cancer Cell, 3, 589–601 (2003).
• 68) Boosani CS, Varma AK, Sudhakar A. Validation of different systems for tumstatin expression and its in vitro and in vivo activities. J. Cancer Sci. Ther., 2009, 8–18 (2010).
• 69) Hwang-Bo J, Park JH, Chung IS. Tumstatin induces apoptosis mediated by Fas signaling pathway in oral squamous cell carcinoma SCC-VII cells. Oncol. Lett., 10, 1016–1022 (2015).
• 70) Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alpha(v)beta(3) integrin binding sites on tumstatin regulate distinct anti-tumor properties. J. Biol. Chem., 275, 23745–23750 (2000).
• 71) Maeshima Y, Manfredi M, Reimer C, Holthaus KA, Hopfer H, Chandamuri BR, Kharbanda S, Kalluri R. Identification of the anti-angiogenic site within vascular basement membrane-derived tumstatin. J. Biol. Chem., 276, 15240–15248 (2001).
• 72) Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha(v)beta(3) and alpha(5) beta(1) integrins. Proc. Natl. Acad. Sci. U.S.A., 100, 4766–4771 (2003).
• 73) Wang Y, Yin RF, Teng JS. Tumstatin induces apoptosis and stimulates phosphorylation of p65NF-kappaB in human osteoblastic osteosarcoma Saos-2 cells. Oncol. Rep., 35, 3403–3408 (2016).
• 74) Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science, 295, 140–143 (2002).
• 75) Pasco S, Monboisse JC, Kieffer N. The alpha 3(IV)185–206 peptide from the noncollagenous domain 1 of type IV collagen interacts with a novel binding site on the beta 3 subunit of integrin alpha(v)beta(3) and stimulates focal adhesion kinase and phosphatidylinositol 3-kinase phosphorylation. J. Biol. Chem., 275, 32999–33007 (2000).
• 76) Borza CM, Pozzi A, Borza DB, Pedchenko V, Hellmark T, Hudson BG, Zent R. Integrin alpha(3)beta(1), a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant inhibitor for integrin alpha(v)beta(3). J. Biol. Chem., 281, 20932–20939 (2006).
• 77) Maeshima Y, Yerramalla UL, Dhanabal M, Holthaus KA, Barbashov S, Kharbanda S, Reimer C, Manfredi M, Dickerson WM, Kalluri R. Extracellular matrix-derived peptide binds to alpha(v)beta(3) integrin and inhibits angiogenesis. J. Biol. Chem., 276, 31959–31968 (2001).
• 78) Van der Velden J, Harkness LM, Barker DM, Barcham GJ, Ugalde CL, Koumoundouros E, Bao H, Organ LA, Tokanovic A, Burgess JK, Snibson KJ. The effects of tumstatin on vascularity, airway inflammation and lung function in an experimental sheep model of chronic asthma. Sci. Rep., 6, 26309 (2016).
• 79) Yamamoto Y, Maeshima Y, Kitayama H, Kitamura S, Takazawa Y, Sugiyama H, Yamasaki Y, Makino H. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes, 53, 1831–1840 (2004).
• 80) Nikolova A, Ablasser K, Wyler von Ballmoos MC, Poutias D, Kaza E, McGowan FX, Moses MA, Del Nido PJ, Friehs I. Endogenous angiogenesis inhibitors prevent adaptive capillary growth in left ventricular pressure overload hypertrophy. Ann. Thorac. Surg., 94, 1509–1517 (2012).
• 81) Yasuda J, Okada M, Yamawaki H. T3 peptide, an active fragment of tumstatin, inhibits H₂O₂-induced apoptosis in H9c2 cardiomyoblasts. Eur. J. Pharmacol., 807, 64–70 (2017).
• 82) Yasuda J, Fukui K, Okada M, Yamawaki H. T3 peptide, a fragment of tumstatin, stimulates proliferation and migration of cardiac fibroblasts through activation of Akt signaling pathway. Naunyn Schmiedebergs Arch. Pharmacol., 390, 1135–1144 (2017).
• 83) Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP. Endostatin induces endothelial cell apoptosis. J. Biol. Chem., 274, 11721–11726 (1999).
• 84) Faye C, Moreau C, Chautard E, Jetne R, Fukai N, Ruggiero F, Humphries MJ, Olsen BR, Ricard-Blum S. Molecular interplay between endostatin, integrins, and heparan sulfate. J. Biol. Chem., 284, 22029–22040 (2009).
• 85) Karumanchi SA, Jha V, Ramchandran R, Karihaloo A, Tsiokas L, Chan B, Dhanabal M, Hanai JI, Venkataraman G, Shriver Z, Keiser N, Kalluri R, Zeng H, Mukhopadhyay D, Chen RL, Lander AD, Hagihara K, Yamaguchi Y, Sasisekharan R, Cantley L, Sukhatme VP. Cell surface glypicans are low-affinity endostatin receptors. Mol. Cell, 7, 811–822 (2001).
• 86) Kim YM, Hwang S, Kim YM, Pyun BJ, Kim TY, Lee ST, Gho YS, Kwon YG. Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J. Biol. Chem., 277, 27872–27879 (2002).
• 87) Nguyen TM, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. J. Cell. Mol. Med., 13 (9B), 3687–3698 (2009).
• 88) Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo C, Pihlajaniemi T, Alitalo K, Vuori K. Interaction of endostatin with integrins implicated in angiogenesis. Proc. Natl. Acad. Sci. U.S.A., 98, 1024–1029 (2001).
• 89) Zhang Y, Zhang J, Jiang D, Zhang D, Qian Z, Liu C, Tao J. Inhibition of T-type Ca²⁺ channels by endostatin attenuates human glioblastoma cell proliferation and migration. Br. J. Pharmacol., 166, 1247–1260 (2012).
• 90) Li C, Harris MB, Venema VJ, Venema RC. Endostatin induces acute endothelial nitric oxide and prostacyclin release. Biochem. Biophys. Res. Commun., 329, 873–878 (2005).
• 91) Sunshine SB, Dallabrida SM, Durand E, Ismail NS, Bazinet L, Birsner AE, Sohn R, Ikeda S, Pu WT, Kulke MH, Javaherian K, Zurakowski D, Folkman JM, Rupnick M. Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition. Proc. Natl. Acad. Sci. U.S.A., 109, 11306–11311 (2012).
• 92) Nishimoto T, Mlakar L, Takihara T, Feghali-Bostwick C. An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model. Int. Immunopharmacol., 28, 1102–1105 (2015).
• 93) Wan YY, Tian GY, Guo HS, Kang YM, Yao ZH, Li XL, Liu QH, Lin DJ. Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats. Respir. Res., 14, 56 (2013).
• 94) Hu W, Xia LJ, Chen FH, Wu FR, Tang J, Chen CZ, Jiang S, Chen HH. Recombinant human endostatin inhibits adjuvant arthritis by down-regulating VEGF expression and suppression of TNF-alpha, IL-1beta production. Inflamm. Res., 61, 827–835 (2012).
• 95) Kurosaka D, Yoshida K, Yasuda J, Yasuda C, Noda K, Furuya K, Ukichi T, Kingetsu I, Joh K, Yamaguchi N, Saito S, Yamada A. The effect of endostatin evaluated in an experimental animal model of collagen-induced arthritis. Scand. J. Rheumatol., 36, 434–441 (2007).
• 96) Fu Y, Tang H, Huang Y, Song N, Luo Y. Unraveling the mysteries of endostatin. IUBMB Life, 61, 613–626 (2009).
• 97) Han Q, Fu Y, Zhou H, He Y, Luo Y. Contributions of Zn(II)-binding to the structural stability of endostatin. FEBS Lett., 581, 3027–3032 (2007).
• 98) Liang R, Xie HY, Lin Y, Li Q, Yuan CL, Liu ZH, Li YQ. Intraperitoneal perfusion therapy of endostar combined with platinum chemotherapy for malignant serous effusions: a meta-analysis. Asian Pac. J. Cancer Prev., 16, 8637–8644 (2015).
• 99) Damico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ, Kass DA, Rafaels N, Gao L, Barnes KC, Benza RL, Rand JL, Hamid R, Loyd JE, Robbins IM, Hemnes AR, Chung WK, Austin ED, Drummond MB, Mathai SC, Hassoun PM. Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 191, 208–218 (2015).
• 100) Givvimani S, Kundu S, Narayanan N, Armaghan F, Qipshidze N, Pushpakumar S, Vacek TP, Tyagi SC. TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure. Arch. Physiol. Biochem., 119, 65–74 (2013).
• 101) Givvimani S, Munjal C, Gargoum R, Sen U, Tyagi N, Vacek JC, Tyagi SC. Hydrogen sulfide mitigates transition from compensatory hypertrophy to heart failure. J. Appl. Physiol., 110, 1093–1100 (2011).
• 102) Givvimani S, Munjal C, Tyagi N, Sen U, Metreveli N, Tyagi SC. Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure. PLOS ONE, 7, e32388 (2012).
• 103) Givvimani S, Tyagi N, Sen U, Mishra PK, Qipshidze N, Munjal C, Vacek JC, Abe OA, Tyagi SC. MMP-2/TIMP-2/TIMP-4 versus MMP-9/TIMP-3 in transition from compensatory hypertrophy and angiogenesis to decompensatory heart failure. Arch. Physiol. Biochem., 116, 63–72 (2010).
• 104) Gouya G, Siller-Matula JM, Fritzer-Szekeres M, Neuhold S, Storka A, Neuhofer LM, Clodi M, Hulsmann M, Pacher R, Wolzt M. Association of endostatin with mortality in patients with chronic heart failure. Eur. J. Clin. Invest., 44, 125–135 (2014).
• 105) Mitsuma W, Kodama M, Hanawa H, Ito M, Ramadan MM, Hirono S, Obata H, Okada S, Sanada F, Yanagawa T, Kashimura T, Fuse K, Tanabe N, Aizawa Y. Serum endostatin in the coronary circulation of patients with coronary heart disease and its relation to coronary collateral formation. Am. J. Cardiol., 99, 494–498 (2007).
• 106) Qipshidze N, Metreveli N, Mishra PK, Lominadze D, Tyagi SC. Hydrogen sulfide mitigates cardiac remodeling during myocardial infarction via improvement of angiogenesis. Int. J. Biol. Sci., 8, 430–441 (2012).
• 107) Dziankowska-Bartkowiak B, Waszczykowska E, Dziankowska-Zaboroszczyk E, de Graft-Johnson JE, Zalewska A, Luczynska M, Nowak D. Decreased ratio of circulatory vascular endothelial growth factor to endostatin in patients with systemic sclerosis—association with pulmonary involvement. Clin. Exp. Rheumatol., 24, 508–513 (2006).
• 108) Feldman AL, Tamarkin L, Paciotti GF, Simpson BW, Linehan WM, Yang JC, Fogler WE, Turner EM, Alexander HR Jr, Libutti SK. Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer. Clin. Cancer Res., 6, 4628–4634 (2000).
• 109) Urbańska-Ryś H, Robak T. High serum level of endostatin in multiple myeloma at diagnosis but not in the plateau phase after treatment. Mediators Inflamm., 12, 229–235 (2003).
• 110) Eleuteri E, Di Stefano A, Giordano A, Corra U, Tarro Genta F, Gnemmi I, Giannuzzi P. Prognostic value of angiopoietin-2 in patients with chronic heart failure. Int. J. Cardiol., 212, 364–368 (2016).
• 111) Liou JY, Shyu KG, Lu MJ, Chao HH, Wang BW, Kuan PL. Pericardial fluid and serum levels of vascular endothelial growth factor and endostatin in patients with or without coronary artery disease. J. Formos. Med. Assoc., 105, 377–383 (2006).
• 112) Ueland T, Aukrust P, Nymo SH, Kjekshus J, McMurray JJ, Wikstrand J, Wienhues-Thelen UH, Block D, Zaugg C, Gullestad L. Predictive value of endostatin in chronic heart failure patients with poor kidney function. Cardiology, 130, 17–22 (2015).
• 113) Panchal VR, Rehman J, Nguyen AT, Brown JW, Turrentine MW, Mahomed Y, March KL. Reduced pericardial levels of endostatin correlate with collateral development in patients with ischemic heart disease. J. Am. Coll. Cardiol., 43, 1383–1387 (2004).
• 114) Isobe K, Kuba K, Maejima Y, Suzuki J, Kubota S, Isobe M. Inhibition of endostatin/collagen XVIII deteriorates left ventricular remodeling and heart failure in rat myocardial infarction model. Circ. J., 74, 109–119 (2010).
• 115) Chiang CS, Huang CH, Chieng H, Chang YT, Chang D, Chen JJ, Chen YC, Chen YH, Shin HS, Campbell KP, Chen CC. The Ca_v3.2 T-type Ca²⁺ channel is required for pressure overload-induced cardiac hypertrophy in mice. Circ. Res., 104, 522–530 (2009).
• 116) Huang B, Qin D, Deng L, Boutjdir M, El-Sherif N. Reexpression of T-type Ca²⁺ channel gene and current in post-infarction remodeled rat left ventricle. Cardiovasc. Res., 46, 442–449 (2000).
• 117) Kinoshita H, Kuwahara K, Takano M, Arai Y, Kuwabara Y, Yasuno S, Nakagawa Y, Nakanishi M, Harada M, Fujiwara M, Murakami M, Ueshima K, Nakao K. T-type Ca²⁺ channel blockade prevents sudden death in mice with heart failure. Circulation, 120, 743–752 (2009).
• 118) Martínez ML, Heredia MP, Delgado C. Expression of T-type Ca²⁺ channels in ventricular cells from hypertrophied rat hearts. J. Mol. Cell. Cardiol., 31, 1617–1625 (1999).
• 119) Vassort G, Talavera K, Alvarez JL. Role of T-type Ca²⁺ channels in the heart. Cell Calcium, 40, 205–220 (2006).
• 120) Yasuda J, Okada M, Yamawaki H. Endostatin inhibits T-type Ca²⁺ channel current in guinea pig ventricular myocyte. J. Vet. Med. Sci., 77, 1289–1291 (2015).
• 121) Imoto K, Kumatani S, Okada M, Yamawaki H. Endostatin is protective against monocrotaline-induced right heart disease through the inhibition of T-type Ca²⁺ channel. Pflugers Arch., 468, 1259–1270 (2016).
• 122) Yasuda J, Takada L, Kajiwara Y, Okada M, Yamawaki H. Endostatin inhibits bradykinin-induced cardiac contraction. J. Vet. Med. Sci., 77, 1391–1395 (2015).
• 123) Okada M, Oba Y, Yamawaki H. Endostatin stimulates proliferation and migration of adult rat cardiac fibroblasts through PI3K/Akt pathway. Eur. J. Pharmacol., 750, 20–26 (2015).
• 124) Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Hook M, Reed CC, Iozzo RV. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha(2)beta(1) integrin. J. Cell Biol., 166, 97–109 (2004).
• 125) Goyal A, Gubbiotti MA, Chery DR, Han L, Iozzo RV. Endorepellin-evoked autophagy contributes to angiostasis. J. Biol. Chem., 291, 19245–19256 (2016).
• 126) Goyal A, Pal N, Concannon M, Paul M, Doran M, Poluzzi C, Sekiguchi K, Whitelock JM, Neill T, Iozzo RV. Endorepellin, the angiostatic module of perlecan, interacts with both alpha(2)beta(1) integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism. J. Biol. Chem., 286, 25947–25962 (2011).
• 127) Poluzzi C, Casulli J, Goyal A, Mercer TJ, Neill T, Iozzo RV. Endorepellin evokes autophagy in endothelial cells. J. Biol. Chem., 289, 16114–16128 (2014).
• 128) Woodall BP, Nystrom A, Iozzo RA, Eble JA, Niland S, Krieg T, Eckes B, Pozzi A, Iozzo RV. Integrin alpha(2)beta(1) is the required receptor for endorepellin angiostatic activity. J. Biol. Chem., 283, 2335–2343 (2008).
• 129) Lee B, Clarke D, Al Ahmad A, Kahle M, Parham C, Auckland L, Shaw C, Fidanboylu M, Orr AW, Ogunshola O, Fertala A, Thomas SA, Bix GJ. Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents. J. Clin. Invest., 121, 3005–3023 (2011).
• 130) Jung M, Lord MS, Cheng B, Lyons JG, Alkhouri H, Hughes JM, McCarthy SJ, Iozzo RV, Whitelock JM. Mast cells produce novel shorter forms of perlecan that contain functional endorepellin: a role in angiogenesis and wound healing. J. Biol. Chem., 288, 3289–3304 (2013).
• 131) Cailhier JF, Sirois I, Laplante P, Lepage S, Raymond MA, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hebert MJ. Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis. J. Biol. Chem., 283, 27220–27229 (2008).
• 132) Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV. BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J. Biol. Chem., 280, 7080–7087 (2005).
• 133) Soulez M, Pilon EA, Dieude M, Cardinal H, Brassard N, Qi S, Wu SJ, Durocher Y, Madore F, Perreault C, Hebert MJ. The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection. Circ. Res., 110, 94–104 (2012).
• 134) Zoeller JJ, McQuillan A, Whitelock J, Ho SY, Iozzo RV. A central function for perlecan in skeletal muscle and cardiovascular development. J. Cell Biol., 181, 381–394 (2008).
• 135) Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxid. Redox Signal., 18, 1100–1113 (2013).
• 136) Oka T, Akazawa H, Naito AT, Komuro I. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ. Res., 114, 565–571 (2014).
• 137) Awada HK, Johnson NR, Wang Y. Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. J. Control. Release, 207, 7–17 (2015).
• 138) Kim D, Ku SH, Kim H, Jeong JH, Lee M, Kwon IC, Choi D, Kim SH. Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA. J. Control. Release, 243, 182–194 (2016).
• 139) Ma Y, de Castro Bras LE, Toba H, Iyer RP, Hall ME, Winniford MD, Lange RA, Tyagi SC, Lindsey ML. Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling. Pflugers Arch., 466, 1113–1127 (2014).
• 140) van Nieuwenhoven FA, Turner NA. The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction. Vascul. Pharmacol., 58, 182–188 (2013).
• 141) Marunouchi T, Tanonaka K. Cell death in the cardiac myocyte. Biol. Pharm. Bull., 38, 1094–1097 (2015).
• 142) Moe GW, Marin-Garcia J. Role of cell death in the progression of heart failure. Heart Fail. Rev., 21, 157–167 (2016).
• 143) Buckley CL, Stokes AJ. Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. Channels (Austin), 5, 367–374 (2011).
• 144) Camacho Londoño JE, Tian Q, Hammer K, Schroder L, Camacho Londoño J, Reil JC, He T, Oberhofer M, Mannebach S, Mathar I, Philipp SE, Tabellion W, Schweda F, Dietrich A, Kaestner L, Laufs U, Birnbaumer L, Flockerzi V, Freichel M, Lipp P. A background Ca²⁺ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. Eur. Heart J., 36, 2257–2266 (2015).
• 145) Glynn P, Musa H, Wu X, Unudurthi SD, Little S, Qian L, Wright PJ, Radwanski PB, Gyorke S, Mohler PJ, Hund TJ. Voltage-gated sodium channel phosphorylation at Ser571 regulates late current, arrhythmia, and cardiac function in vivo. Circulation, 132, 567–577 (2015).
• 146) Marionneau C, Brunet S, Flagg TP, Pilgram TK, Demolombe S, Nerbonne JM. Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K⁺ currents with left ventricular hypertrophy. Circ. Res., 102, 1406–1415 (2008).
• 147) Nakayama H, Bodi I, Correll RN, Chen X, Lorenz J, Houser SR, Robbins J, Schwartz A, Molkentin JD. Alpha(1)G-dependent T-type Ca²⁺ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice. J. Clin. Invest., 119, 3787–3796 (2009).
• 148) Nakayama H, Bodi I, Maillet M, DeSantiago J, Domeier TL, Mikoshiba K, Lorenz JN, Blatter LA, Bers DM, Molkentin JD. The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. Circ. Res., 107, 659–666 (2010).
• 149) Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J., 20, 1660–1670 (2006).
• 150) Toischer K, Hartmann N, Wagner S, Fischer TH, Herting J, Danner BC, Sag CM, Hund TJ, Mohler PJ, Belardinelli L, Hasenfuss G, Maier LS, Sossalla S. Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease. J. Mol. Cell. Cardiol., 61, 111–122 (2013).
• 151) Wang Y, Cheng J, Chen G, Rob F, Naseem RH, Nguyen L, Johnstone JL, Hill JA. Remodeling of outward K⁺ currents in pressure-overload heart failure. J. Cardiovasc. Electrophysiol., 18, 869–875 (2007).
• 152) Tjin Tham Sjin RM, Satchi-Fainaro R, Birsner AE, Ramanujam VM, Folkman J, Javaherian K. A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity. Cancer Res., 65, 3656–3663 (2005).
• 153) Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K. Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy. Clin. Cancer Res., 14, 1487–1493 (2008).
• 154) Hu S, Zhang Y. Endostar-loaded PEG-PLGA nanoparticles: in vitro and in vivo evaluation. Int. J. Nanomedicine, 5, 1039–1048 (2010).
• 155) Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am. J. Hypertens., 23, 460–468 (2010).
• 156) Barrese V, Taglialatela M. New advances in beta-blocker therapy in heart failure. Front. Physiol., 4, 323 (2013).
• 157) Amin P, Singh M, Singh K. β-adrenergic receptor-stimulated cardiac myocyte apoptosis: role of β1 integrins. J. Signal Transduct., 2011, 179057 (2011).
• 158) Bomback AS, Toto R. Dual blockade of the renin-angiotensin-aldosterone system: beyond the ACE inhibitor and angiotensin-II receptor blocker combination. Am. J. Hypertens., 22, 1032–1040 (2009).
• 159) Hong F, Ming L, Yi S, Zhanxia L, Yongquan W, Chi L. The antihypertensive effect of peptides: a novel alternative to drugs? Peptides, 29, 1062–1071 (2008).
• 160) Farias SL, Sabatini RA, Sampaio TC, Hirata IY, Cezari MH, Juliano MA, Sturrock ED, Carmona AK, Juliano L. Angiotensin I-converting enzyme inhibitor peptides derived from the endostatin-containing NC1 fragment of human collagen XVIII. Biol. Chem., 387, 611–616 (2006).
• 161) Dostal DE, Feng H, Nizamutdinov D, Golden HB, Afroze SH, Dostal JD, Jacob JC, Foster DM, Tong C, Glaser S, Gerilechaogetu F. Mechanosensing and regulation of cardiac function. J. Clin. Exp. Cardiolog., 5, 314 (2014).
• 162) Bettink SI, Werner C, Chen CH, Muller P, Schirmer SH, Walenta KL, Bohm M, Laufs U, Friedrich EB. Integrin-linked kinase is a central mediator in angiotensin II type 1- and chemokine receptor CXCR4 signaling in myocardial hypertrophy. Biochem. Biophys. Res. Commun., 397, 208–213 (2010).