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Volume 123 (2004)
- Issue 6 Pages 382-
- Issue 5 Pages 311-
- Issue 4 Pages 235-
- Issue 3 Pages 134-
- Issue 2 Pages 55-
- Issue 1 Pages 5-
Volume 123, Issue 2
Displaying 1-8 of 8 articles from this issue
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Reviews: Molecular Basis of Heart Failure and its Treatments
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Tomie KAWADA, Mikio NAKAZAWA, Teruhiko TOYO-OKAArticle type: Reviews
2004 Volume 123 Issue 2 Pages 55-62
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSTo clarify the precise mechanism for the progression of advanced heart failure (AdHF), we assessed the scheme in two HF models, using (I) TO-2 strain hamsters sharing common genetic and clinical features to human families with the δ-sarcoglycan (SG) gene mutation and (II) administration of a high-dose (HD) of isoproterenol (Isp) to normal rats. δ-SG is a component in dystrophin (Dys)-related proteins that stabilize the sarcolemma (SL) during repeated heart beats. In TO-2, we followed time course of hemodynamics, immunostaining and Western blotting of Dys and in situ SL permeability by Evans blue uptake with or without the gene therapy. Dys was age-dependently translocated from the SL to myoplasm (MP) where the SL instability accompanied the fragmention of Dys. By gene therapy to supplement the normal δ-SG gene in hearts in vivo, we found that Dys translocation was selectively improved in cardiomyocytes expressing the δ-SG transgene, where the SL fragility was ameliorated. Most importantly, the survival period of the animals was prolonged. Furthermore, Dys but not δ-SG was also time-dependently shifted with a HD of Isp from the SL to MP and fragmented, while δ-SG was preserved intact. We present a novel paradigm that disruption of Dys, but not δ-SG per se, leads to AdHF irrespective of hereditary or acquired origin.
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Makoto KODAMA, Hitoshi TACHIKAWA, Takeshi KASHIMURA, Manabu HAYASHI, T ...Article type: Reviews
2004 Volume 123 Issue 2 Pages 63-70
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSChronic heart failure is a slowly progressive disease. Hemodynamic deterioration activates various neuro-humoral factors and increases stresses, such as catecholamine, angiotensin II (AII), cytokines, endothelin, wall stress, ischemia, tachycardia, and oxidative stress. These factors affect the myocardium to cause phenotype switching, leading to ventricular remodeling. We investigated the effects of pharmacological blocking for neuro-humoral factors in rats with dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) was elicited in Lewis rats by immunization with cardiac myosin. After acute inflammation healed, rats were treated with angiotensin converting enzyme inhibitors (ACEI), type 1 AII receptor blockers, and amiodarone. These agents had favorable effects on hemodynamics and myocardial contractility, prevented fibrosis, suppressed the expression of ANP, and reversed phenotypic change of cardiac myosin. AII receptor blockers were less effective than ACEI. In order to prevent ventricular remodeling in chronic heart failure, wide and complete blocking of neuro-humoral factors is important.
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Kouichi TANONAKA, Wakako TOGA, Satoshi TAKEOArticle type: Reviews
2004 Volume 123 Issue 2 Pages 71-76
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSHeat shock protein (Hsp) 70s including Hsp72 and Hsp73 are suggested to play an important role in the cardioprotection against stress-induced functional damage. Myocardial tolerance against ischemia/reperfusion injury is increased when myocardial Hsp72 is accumulated after an exposure of normal animals to heat shock. Post-ischemic contractile recovery is improved in the perfused heart of Hsp72-overexpressed mice. However, the role of Hsp72 and Hsp73 in the failing heart following acute myocardial infarction remains unclear. The present study was undertaken to determine whether Hsp72 and Hsp73 production may contribute to the protection of cardiac function in rats with chronic heart failure (CHF) following coronary artery ligation (CAL). The rats with CAL revealed the signs of CHF at the 8th week after the operation. The hearts isolated from rats with CHF were perfused and then subjected to heat shock (at 42°C) for 15 min followed by 6-h perfusion (HS group). The cardiac function of the HS group was markedly decreased and the heat shock-induced increase in myocardial Hsp72 and Hsp73 was attenuated after 6-h perfusion. In the CAL rat treated with the ACE inhibitor trandolapril from the 2nd to the 8th week, induction of Hsp70s was preserved and heat stress-induced reduction in cardiac function was attenuated. The results suggest that a reduction in the production of Hsp70s may play a significant role in the decrease in contractile function during the development of heart failure.
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Yoshiro YOSHIKAWA, Miyako TAKAKIArticle type: Reviews
2004 Volume 123 Issue 2 Pages 77-86
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSWe investigated left ventricular (LV) mechanoenergetics in acute and chronic failing hearts, induced by high Ca2+, ischemic-reperfusion injury, diabetes mellitus (DM), and hypothyroidism, using cross-circulated excised rat heart preparations. After high Ca2+ or ischemic-reperfusion, there was a contractile failure associated with a parallel downward shift of the linear relation between myocardial O2 consumption per beat (VO2) and systolic pressure-volume area (PVA). This result indicated a decrease in VO2 for total Ca2+ handling in E-C coupling. We found proteolysis of a cytoskeletal protein, α-fodrin. A calpain inhibitor significantly suppressed contractile failure, decreased VO2 for total Ca2+ handling, and membrane α-fodrin degradation. In DM, the LV relaxation rate was significantly slower, resulting in the decreased O2 consumption per min for total Ca2+ handling in E-C coupling. In hypothyroidism, there were systolic and diastolic failures associated with the decreased O2 consumption per beat for total Ca2+ handling in E-C coupling. The protein level of sarcoplasmic reticulum Ca2+ ATPase (SERCA2) was significantly lower in DM and hypothyroidism. We conclude that suppression of O2 consumption for total Ca2+ handling, mainly utilized by SERCA2, is a major cause of failing hearts, mediated through degradation of membrane α-fodrin via activation of calpain or suppressed expression of SERCA2.
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Yoichiro KUSAKARI, Shuta HIRANO, Kenichi HONGO, Hiroyuki NAKAYAMA, Kin ...Article type: Reviews
2004 Volume 123 Issue 2 Pages 87-93
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSCytosolic Ca2+ is a key regulator of excitation-contraction coupling in myocardium. Myocardial contractile dysfunction in heart failure is characterized by a decrease in contraction and prolonged relaxation. These alterations are mainly due to changes in 1) intracellular Ca2+ transients (CaT), 2) Ca2+ sensitivity of the contractile elements, and/or 3) contractile proteins. It is useful to investigate the relationship between CaT and contraction for understanding of the mechanism of contractile dysfunction in heart failure. There are many reports regarding the alterations in CaT, Ca2+ sensitivity, and contractile proteins in heart failure. Changes in the activity of the sarcoplasmic Ca2+ pump protein, SERCA2a, may be involved in the altered contractility in heart failure. We generated cardiac-restricted overexpression of SERCA2a transgenic mice (TG) and non-transgenic littermates (NTG). To investigate the role of SERCA2a activity for ischemic heart, we used acidosis as a model of acute contractile dysfunction. During acidosis and recovery from acidosis, the peaks of CaT and tension in TG were significantly larger than those in NTG. These results suggest that an increase in the activity of SERCA2a could be beneficial to preserve contractility during acidosis and recovery. Thus, a disturbance of the intracellular Ca2+ homeostasis is one of the key factors for the contractile dysfunction in heart failure.
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Award Lecture
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Masabumi MINAMIArticle type: Award Lecture
2004 Volume 123 Issue 2 Pages 95-104
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSWe cloned κ and µ opioid receptor cDNAs. Using these cDNAs, first, we examined the molecular mechanism for the subtype selectivity of opioid ligands, especially a µ-selective ligand DAMGO. Binding experiments using various chimera and mutated receptors revealed that DAMGO discriminates between µ and δ receptors by recognizing the difference in only one amino acid residue, that is, N127 in µ and K108 in δ, at the first extracellular loop, and that it distinguishes between µ and κ receptors by the difference in four amino acid residues at the third extracellular loop. Second, we established the cell lines expressing the cloned µ, δ, or κ receptor and elucidated the pharmacological properties, that is, binding affinity and agonistic activity of several opioid agonists. Third, distribution of the mRNAs for µ, δ, and κ receptors in the brain, spinal cord, and DRG was examined by in situ hybridization histochemistry (ISHH). Double ISHH demonstrated that most of the substance P-producing DRG neurons express the µ receptor. Recently, we are interested in the emotional aspect of pain and its regulation by opioids. Behavioral and microdialysis studies showed that sustained pain evoked by the intraplanter injection of formalin induced conditioned place aversion through the increment of glutamate release followed by the activation of NMDA receptors in the basolateral nucleus of amygdala (BLA). Intra-BLA injection of morphine suppressed the place aversion by inhibiting the glutamate release.
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Review
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Takashi KANEMATSU, Miho TERUNUMA, Hidefumi GOTO, Akiko KURATANI, Masat ...Article type: Review
2004 Volume 123 Issue 2 Pages 105-112
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSγ-Aminobutyric acidA (GABAA) receptors mediate most of the fast inhibitory neurotransmission in the central nervous system. These ligand-gated ion channels are crucial in the control of cell and network activity. Therefore, modulating their function or cell surface stability will have major consequences for neuronal excitation. This review highlights recent findings on the regulation of GABAA-receptor expression and function, focusing on the mechanisms of sorting, targeting, synaptic clustering, and endocytic events of GABAA receptors, all which are regulated by their associated proteins. Now these topics are an area of active interest in studies on inhibitory neurotransmission.
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Akihiko KATO, Hiroyuki SUGIYAMAArticle type: Review
2004 Volume 123 Issue 2 Pages 113-122
Published: 2004
Released on J-STAGE: January 23, 2004
JOURNAL FREE ACCESSAMPA receptors play central roles for synaptic transmission in the central nervous system in mammals. Here we review the molecular mechanisms for how AMPA receptor subunits are correctly assembled, how AMPA receptors are conveyed to dendrites, and how AMPA receptors are exposed in postsynaptic sites. We also discuss the molecular mechanisms of synaptic plasticity that is the cellular basis of learning and memory.
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