Although several risk factors including hypertension, cardiac hypertrophy, coronary artery disease, and diabetes are known to result in heart failure, elderly subjects are more susceptible to myocardial infarction and more likely to develop heart failure. This article is intended to discuss that cardiac dysfunction in hearts failing due to myocardial infarction and aging is associated with cardiac remodeling and defects in the subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR), and myofibrils. Despite some differences in the pattern of heart failure due to myocardial infarction and aging with respect to their etiology and sequence of events, evidence has been presented to show that subcellular remodeling plays a critical role in the occurrence of intracellular Ca(2+)-overload and development of cardiac dysfunction in both types of failing heart. In particular, alterations in gene expression for SL and SR proteins induce Ca(2+)-handling abnormalities in cardiomyocytes, whereas those for myofibrillar proteins impair the interaction of Ca(2+) with myofibrils in hearts failing due to myocardial infarction and aging. In addition, different phosphorylation mechanisms, which regulate the activities of Ca(2+)-cycling proteins in SL and SR membranes as well as Ca(2+)-binding proteins in myofibrils, become defective in the failing heart. Accordingly, it is suggested that subcellular remodeling involving defects in Ca(2+)-handling and Ca(2+)-binding proteins as well as their regulatory mechanisms is intimately associated with cardiac remodeling and heart failure due to myocardial infarction and aging.
Antiplatelet agents, sarpogrelate (SAR), a 5-HT2A receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE-III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks. Sham-operated animals served as controls. At end of the treatment period, haemodynamic measurements were performed and the left ventricle was processed for the determination of sarcoplasmic reticulum (SR) Ca2+-uptake and -release activities, and expression of SR Ca2+-pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of α- and β-myosin heavy chain (MHC) isoforms, and phosphorylation of phospholamban and cardiac troponin-I (c Tn-I). Marked haemodynamic changes in the MI-induced CHF were associated with depressions in SR Ca +-uptake and -release activities as well as in protein content and gene expression for SR proteins. Furthermore, myofibrillar Ca2+-stimulated ATPase activity, as well as protein content and gene expression for α-MHC were decreased whereas those for β-MHC were increased in the failing heart. Also, phosphorylation levels of phospholamban and cTn-I were reduced in failing hearts. The MI-associated changes in cardiac function, SR and myofibillar activities, as well as SR and myofibrillar protein and gene expression were attenuated by treatment with SAR or CIL. The results suggest that SAR and CIL improve cardiac function by ameliorating subcellular remodelling in the failing heart and indicate the potential therapy of CHF with antiplatelet agents.
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