Mitochondrial-derived reactive oxygen species (mtROS) is one of the major sources of cellular ROS, and excessive mtROS is associated with atherosclerosis progression in both human and mouse models. This review aims to summarize the most recent studies showing the existence, the causes and pathological consequences of excessive mtROS in atherosclerosis. Despite numerous association and causation studies demonstrating the importance of mtROS in atherosclerosis progression, the failure of antioxidant therapy in human randomized clinical trials demands more definitive, cell-type specific investigations. Better mechanistic understanding of mtROS in atherosclerosis may lead to more effective therapeutic strategies.

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Recent major advances in medical science have introduced a wide variety of treatments against atherosclerosis-based cardiovascular diseases, which has led to a significant reduction in mortality associated with these diseases. However, atherosclerosis-based cardiovascular disease remains a leading cause of death. Furthermore, progress in medical science has demonstrated the pathogenesis of cardiovascular disease to be complicated, with a wide variety of underlying factors. Among these factors, stress is thought to be pivotal. Several types of stress are involved in the development of cardiovascular disease, including oxidative stress, mental stress, hemodynamic stress and social stress. Accumulating evidence indicates that traditional risk factors for atherosclerosis, including diabetes, hyperlipidemia, hypertension and smoking, induce oxidative stress in the vasculature. Oxidative stress is implicated in the pathogenesis of endothelial dysfunction, atherogenesis, hypertension and remodeling of blood vessels. Meanwhile, mental stress is a well-known major contributor to the development of cardiovascular disease. The cardiovascular system is constantly exposed to hemodynamic stress by the blood flow and/or pulsation, and hemodynamic stress exerts profound effects on the biology of vascular cells and cardiomyocytes. In addition, social stress, such as that due to a lack of social support, poverty or living alone, has a negative impact on the incidence of cardiovascular disease. Furthermore, there are interactions between mental, oxidative and hemodynamic stress. The production of reactive oxygen species is increased under high levels of mental stress in close association with oxidative stress. These stress responses and their interactions play central roles in the pathogenesis of atherosclerosis-based cardiovascular disease. Accordingly, the pathophysiological and clinical implications of stress are discussed in this article.

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Krüppel-like factor 4(KLF4) is a zinc-finger transcription factor that plays a key role in cellular differentiation and proliferation during normal development and in various diseases, such as cancer. The results of recent studies have revealed that KLF4 is expressed in multiple vascular cell types, including phenotypically modulated smooth muscle cells(SMCs), endothelial cells and monocytes/macrophages and contributes to the progression of vascular diseases by activating or repressing the transcription of multiple genes via its associations with a variety of partner proteins. For example, KLF4 decreases the expression of markers of SMC differentiation by interacting with serum response factor, ELK1 and histone deacetylases. KLF4 also suppresses SMC proliferation by associating with p53. In addition, KLF4 enhances arterial medial calcification in concert with RUNX2. Furthermore, endothelial KLF4 represses arterial inflammation by binding to nuclear factor-κB. This article summarizes the role of KLF4 in vascular disease with a particular focus on in vivo studies and reviews recent progress in our understanding of the regulatory mechanisms involved in KLF4- mediated gene transcription.

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Aim: To properly assess the guidance for perioperative management, we undertook a clinical epidemiology study with the primary aim of evaluating the incidence of perioperative vascular complications and their associated factors in a cohort of Japanese patients who underwent non-cardiac surgery in a tertiary medical care center.
Methods: This observational study comprised two parts. In the first part, thrombotic and bleeding events and their risk factors in the perioperative period were evaluated in a total of 2,654 consecutive patients. In the second part, perioperative changes in coagulation-related factors, including the thrombin-antithrombin complex(TAT) and platelet aggregation activity, were serially characterized in 82 individuals randomly chosen from the consecutive patients.
Results: The incidence of perioperative vascular complications was as follows: 1.0% for major bleeding, 0.21% for stroke and 0.21% for venous thromboembolism. No episodes of symptomatic myocardial infarction were identified in the studied population. Perioperative changes in coagulationrelated factors were found to be complex and correlated in the mixed direction of pro- and anticoagulation. The TAT values showed prolonged(across postoperative days 1-5) and prominent(＞116% increase) perioperative activation of coagulation, whereas global coagulation parameters, such as the prothrombin time, showed a tendency of anticoagulation in the immediate postoperative period.
Conclusions: Our data confirm the relatively low incidence of perioperative vascular complications in the general Japanese non-cardiac surgical population. Given the delicate balance between thrombotic and bleeding events, it is important to comprehensively understand the associations between the patient’s baseline risk factors and vascular complications for effective clinical management.

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Aims: To investigate whether metabolic syndrome(MetS) can predict the new onset of carotid plaque or the progression of carotid intima-media thickness(C-IMT) and identify other associated factors in an elderly population without evidence of early carotid atherosclerosis.
Methods: B-mode carotid ultrasonography was used to assess the presence of carotid plaque and the C-IMT at baseline and follow-up. Participants with carotid plaque or an increased C-IMT(≥1.0mm) at baseline were excluded from the study. The new occurrence of carotid plaque, defined as early carotid atherosclerosis and the progression of C-IMT, was evaluated. Multiple regression analyses were used to determine predictors of these findings.
Results: A total of 370participants over 60years of age(median age=66years, 34.1% men) were enrolled. After a median follow-up period of 25 months, 64participants(17.3%) had newly developed carotid plaque. After adjusting for variables determined to be statistically significant in univariate analyses, a multivariable regression analysis showed that predictors of newly developed carotid plaque were metabolic syndrome(hazard ratio [HR]=1.916; 95% confidence interval [CI]: 1.059-3.466), white blood cell count(HR=1.313; 95% CI: 1.094-1.576) and vitamin B12(HR=1.001; 95% CI: 1.000-1.002) and total cholesterol(HR=1.009; 95% CI: 1.001-1.017) levels. A multiple linear regression analysis showed that the rate of change for C-IMT tended to be associated with the development of metabolic syndrome.
Conclusions: Metabolic syndrome is associated with the progression of early carotid atherosclerosis in the general population, suggesting that metabolic syndrome plays an important role in initiating the atherosclerotic process.

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Aim: It is well known that platelet volume indices are associated with adverse outcomes following percutaneous coronary intervention(PCI). In this study, we investigated the hypothesis whether the association between platelet size and clinical outcomes is the result of high residual platelet reactivity after antiplatelet therapy in patients with large platelets.
Methods: Between February 2010 and December 2011, a total of 462 consecutive patients with coronary artery disease who were scheduled to undergo planned PCI were enrolled in this study. The degree of platelet aggregation induced by arachidonic acid(AA) and adenosine diphosphate(ADP) was assessed using the Multiple Electrode Platelet Aggregometry(Multiplate^®, Dynabyte, Munich, Germany)(MEA) test. We simultaneously measured the mean platelet volume(MPV) in the same period(Sysmex XE-2100, Mundelein, IL).
Results: The study population consisted of 462 consecutive patients, including 371 stable angina patients and 91 acute coronary syndrome patients. The patients with large platelets(upper quintile of MPV ≥10.6 fL) had significantly high residual platelet reactivity after both aspirin(MEA ASP 9 [5-14] Units vs. 13 [8-18.5] Units, p＜0.001) and clopidogrel(MEA ADP 21 [15-30] Units vs. 24 [18.5-40] Units, p=0.003) treatment. According to a multivariate analysis, having large platelets was independently associated with high residual platelet reactivity after both aspirin (OR 2.52, 95% CI 1.50-4.24, p＜0.001) and clopidogrel(OR 2.86, 95% CI 1.59-5.15, p＜0.001) treatment. Platelet volume indices were not associated with any differences in the incidence of major adverse cardiac events during follow-up.
Conclusions: Platelets with a higher volume are associated with high residual platelet reactivity after conventional dual antiplatelet therapy.

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Aims: The serum resistin level is associated with the incidence of ischemic heart disease in the general population. We analyzed the associations between serum resistin and fat intake, serum lipid concentrations and adiposity in the general population.
Methods: A cross-sectional study of 6,637 randomly recruited adults was conducted. The resistin levels were measured in thawed aliquots of serum using an enzyme immunoanalysis technique.
Results: The resistin level exhibited a positive nonparametric correlation with saturated fat intake(p＜0.001) and an inverse correlation with adherence to the Mediterranean diet(p＜0.001), monounsaturated fat intake(p＜0.05), total serum cholesterol(p＜0.001), non-HDL cholesterol(p＜0.001), LDL cholesterol(p＜0.001), body mass index(p＜0.001), waist circumference(p＜0.001) and the waist/height ratio(p＜0.001). An elevated resistin concentration(fifth quintile) was associated with adherence to the Mediterranean diet(OR=0.82 CI_95%=0.71-0.93), saturated fat intake(OR=1.34 CI_95%=1.16-1.56), monounsaturated fat intake(OR=0.88 CI_95%=0.78-0.99), a total cholesterol level of ≥200 mg/dL(OR=0.81 CI_95%=0.72-0.91), a low HDL cholesterol level(OR=0.84 CI_95%= 0.76-0.93), a high non-HDL cholesterol level(OR=0.84 CI_95%=0.72-0.99), a high LDL cholesterol level(OR=0.82 CI_95%=0.70-0.97) and a waist/height ratio of ≥0.55(OR=0.76 CI_95%=0.67-0.85). The multivariate models corroborated the positive associations between the resistin level and saturated fat intake(p＜0.001) and serum triglycerides(p=0.004) and the inverse associations between the resistin level and adherence to the Mediterranean diet(p=0.002), total serum cholesterol(p＜ 0.001) and cholesterol fractions and the waist/height ratio(p=0.02).
Conclusions: In the general population, the serum resistin level is associated with fat intake: positively with saturated fat intake and inversely with monounsaturated fat intake. As a consequence, the resistin level is also inversely associated with adherence to the Mediterranean diet. In addition, the resistin level is inversely associated with the serum cholesterol level and adiposity.

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Aim: Vascular calcification, an independent risk factor for cardiovascular disease in patients with chronic kidney disease(CKD), refers to the mineralization of vascular smooth muscle cells(VSMCs) caused by phenotypic changes toward osteoblast-like cells. DNA methylation, mediated by DNA methyltransferases(DNMTs), plays an important role in the differentiation of osteoblasts. We herein assessed the effects of a DNMT inhibitor on phenotypic changes in VSMCs and the development of vascular calcification.
Methods: The effects of 5-aza´-2-deoxycytidine(5-aza-dC), a DNMT inhibitor, on human aortic smooth muscle cells(HASMCs) were evaluated. The expression and DNA methylation status of osteogenic genes were determined using RT-qPCR and bisulfite sequencing, respectively. Mineralization of HASMCs was induced by high concentrations of inorganic phosphate(Pi), as confirmed by quantitation of the calcium levels and von Kossa staining. Moreover, we examined the effects of the suppression of DNMT1 and/or alkaline phosphatase(ALP) on the mineralization of HASMCs.
Results: 5-aza-dC increased the expression and activity of ALP and reduced the DNA methylation levels of the ALP promoter region in the HASMCs. In addition, both treatment with 5-aza-dC and downregulation of the DNMT1 expression promoted the Pi-induced mineralization of HASMCs. Moreover, both treatment with phosphonoformic acid(PFA), a sodium-dependent phosphate transporter inhibitor, and suppression of the ALP expression inhibited the 5-aza-dC-promoted mineralization of HASMCs.
Conclusions: The present study showed that DNMT inhibitors facilitate the Pi-induced development of vascular calcification via the upregulation of the ALP expression along with a reduction in the DNA methylation level of the ALP promoter region.

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Aim: The use of drug-eluting stents has reduced the incidence of in-stent restenosis following percutaneous coronary intervention; however, almost all drugs eluting from polymers on stents induce antiproliferative effects on vascular endothelial and vascular smooth muscle cells. Due to injury of the endothelium and delayed reendothelialization, the risk of thrombosis increases over time. Enhancing rapid reendothelialization after stent placement is important for solving these problems. Basic fibroblast growth factor (bFGF) is one of the most important growth factors involved in vascular lesion formation. In this study, we evaluated the potential of bFGF as a stent coating promoting endothelial cell proliferation.
Methods: Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cultured with various doses of bFGF in vitro, and the effects of bFGF on the degree of cell proliferation and migration were monitored. We also investigated the effects of bFGF on the protein expression of endothelial nitric oxide synthase (eNOS) in HUVECs using Western blotting.
Results: Cell proliferation and migration were promoted in HUVECs by bFGF in a dose- and timedependent manner. On the other hand, bFGF stimulation had little effect on the HASMCs. Basic FGF increased the eNOS protein levels in the HUVECs, with a maximum at 10ng/mL followed by a decline at 100ng/mL.
Conclusions: Basic FGF is a possible candidate stent coating and/or eluting drug material stimulating endothelial cell proliferation and early reendothelialization without excessive vascular smooth muscle cell proliferation.

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Aim: The levels of fasting and postprandial plasma glucose, HbA1c and other risk factors for atherosclerosis have distinct effects in patients with and those without diabetes mellitus. The aim of this study was to determine the impact of diabetic surrogate markers on the endothelial function, arterial stiffness and carotid atherosclerosis in individuals with and without diabetes.
Methods: A total of 320 Japanese subjects(mean age: 61.2±12.1 years) were recruited in this study. Demographic, clinical and laboratory parameters, including 75 g OGTT(155 subjects) results, were examined. The endothelial function was evaluated according to the flow-mediated vasodilation of the brachial artery(%FMD). In addition, arterial stiffness was evaluated according to the brachial-ankle pulse wave velocity(baPWV), and carotid atherosclerotic changes were estimated according to the maximum intima-media thickness(max-IMT) and resistive index of the common carotid artery(CCA-RI). A multiple regression analysis was performed to identify independent determinants of these vascular surrogate markers.
Results: None of the glucose-related parameters were associated with the %FMD. In contrast, the presence of T2DM, the HbA1c level and an increased plasma glucose level at 60 minutes during 75 g OGTT were associated with an increased baPWV. The HbA1c level was also correlated with an increased max-IMT. The fasting plasma glucose(FPG) level and the presence of T2DM correlated with an increased CCA-RI. In the subjects with T2DM, the protective effects of high-density lipoprotein cholesterol(HDL-C) on the %FMD and baPWV were abolished.
Conclusions: Various glucose metabolism parameters have different effects the degree of arterial stiffness and presence of carotid atherosclerosis, but not the endothelial function, suggesting that pharmacological intervention has the potential to preserve the endothelial function in diabetic individuals. In addition, the presence of T2DM blunts the vascular protective effects of HDL-C on the endothelial function and progression of arterial stiffness.

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Aim: The indices of the second derivative of the finger photoplethysmogram(SDPTG) denote stiffness of large arteries, peripheral vascular resistance and vascular aging. However, the association between the autonomic nervous activity and the SDPTG indices has not yet been elucidated.
Methods: The SDPTG and heart rate variability(HRV) were consecutively measured in the sitting position on the day before surgery in 168 patients 18-89 years of age. The relationships between the SDPTG indices(b/a, c/a, d/a and e/a) and HRV indices(power spectral analysis and time domain analysis parameters) were analyzed. The relationships between c/a and atherosclerosis-based conditions and risk factors for atherosclerosis were also evaluated.
Results: The SDPTG index b/a was negatively associated and the d/a index was positively associated with the low-frequency(LF)(R=−0.44 and 0.42, respectively) and high-frequency(HF) components(R=−0.31 and 0.35, respectively). The SDPTG index c/a was also positively associated with the LF(R=0.40) and HF(R=0.44) components. A multivariate regression analysis showed that the LF, HF and heart rate were independent determinants of the c/a. Furthermore, the c/a values were significantly lower in the patients with hypertension, diabetes mellitus and hyperlipidemia than in those without these diseases, and a reduced c/a was significantly associated with increased serum triglyceride and total cholesterol concentrations.
Conclusions: These findings suggest that a decrease in c/a is associated with a reduced baroreflex response of the peripheral vasomotor activity and a decreased cardiac parasympathetic activity. Furthermore, a decrease in c/a was found to be associated with atherosclerosis-based conditions, such as hypertension, diabetes mellitus and hyperlipidemia.

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Aim: In the DIANA(DIAbetes and diffuse coronary NArrowing) study, which evaluated the impact of glucose-lowering therapy in early-stage diabetics with coronary artery disease(CAD), optimal glycemic control resulted in reduced disease progression on angiography. However, despite having a favorable glycemic status, some patients continued to exhibit disease progression. Factors associated with disease progression despite optimal glucose control remain to be elucidated. We sought to investigate clinical characteristics associated with substantial atheroma progression in early-stage diabetic patients with CAD who achieve favorable glycemic control.
Methods: The DIANA study is a prospective randomized trial comparing the effects of lifestyle intervention and treatment with voglibose or nateglinide on disease progression on angiography in 302 CAD patients with impaired glucose tolerance/newly diagnosed diabetes. Of these patients, 137 CAD subjects who achieved optimal glycemic control were stratified according to the presence of disease progression on angiography: progressors(n=64) and non-progressors(n=73). Serial coronary angiography studies and quantitative coronary angiography analyses were conducted to evaluate disease progression. A multivariate analysis was performed to elucidate factors associated with disease progression.
Results: Despite the achievement of optimal glycemic control, atheroma progression was observed in 46% of the study subjects. The progressors exhibited lower decreases in systolic blood pressure(SBP: p=0.007) and reduced baseline total lesion lengths(TLL: p=0.01). The multivariate analysis demonstrated that a greater increase in SBP(p=0.006), treatment without statins(p=0.03) and the baseline TLL(p=0.007) were independently associated with disease progression.
Conclusions: Residual risk factors contribute to the progression of coronary atherosclerosis in early-stage diabetics who exhibit improvements in their glycemic status. The present findings underscore the need to intensively modify multiple risk factors during the early diabetic phase in order to prevent atheroma progression.

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