Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure

Abstract

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.

Cardiac remodelling: General aspects and mechanisms

“…Cardiac remodelling is considered to be not only an adaptive event but also a maladaptive phenomenon. In the acute phase of a myocardial stress, cardiac remodelling acts as an adaptive response that enables the heart to maintain cardiac output; however, after the prolonged stressful stimulus, this continuous process leads to progressive decompensation (8). As a result of this phenomenon, the heart develops cellular changes such as myocyte hypertrophy (2), necrosis (9), apoptosis (10)(11)(12), fibroblast proliferation (13), increased fibrillar collagen (14) and fibrosis (15).…”

Role of intracellular Ca2+ overload in inducing changes in cardiac gene expression

“…It should be emphasized that there are varying degrees of depression in SL, SR and MF gene expression, protein content and functional activities in hearts subjected to ischemia-reperfusion and these alterations have been attributed to the occurrence of intracellular Ca 2+ overload (7)(8)(9)(31)(32)(33)(34)(35)(36)38). Furthermore, intracellular Ca 2+ overload has been suggested to play a critical role in the development of alterations in SL, SR and MF gene expression, protein content and functional activities in hearts failing due to myocardial infarction (1)(2)(3)(4)(5)(6). Although the exact mechanisms by which intracellular Ca 2+ overload induces changes in cardiac gene expression and subsequent subcellular remodelling are not clear at present, a marked increase in the production of different cytokines including tumour necrosis factor and the activation of nuclear factor-kB have been observed in the CP heart (24,39).…”

“…Previous studies have revealed varying degrees of depression in gene expression for SL, SR and MF proteins, as well as defects in subcellular organelles during the development of heart failure in patients and experimental animal models (1)(2)(3)(4)(5)(6). Accordingly, it has been suggested that cardiac dysfunction in failing hearts is due to subcellular remodelling as a consequence of changes in cardiac gene expression (2,(7)(8)(9).…”

Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure

“…Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the elevated matrix metalloproteinase (MMP) activity and myocardial apoptosis are responsible for cardiac remodeling (5)(6)(7). Some previous studies have indicated that both the angiotensinconverting enzyme inhibitors and ß-blocking agents improve cardiac function in failing hearts through attenuating changes in cardiac remodeling such as sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities (4,8,9). It is suggested that cardiac remodeling is an excellent target for the development of improved drug therapy for CHF.…”

“…Noteworthy, left ventricular (LV) remodeling is a dynamic response of the heart to injury and a critical component in the development of CHF. There is increasing evidence that inhibition of cardiac remodeling may be a promising novel therapeutic approach for the treatment of CHF (2)(3)(4). Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the elevated matrix metalloproteinase (MMP) activity and myocardial apoptosis are responsible for cardiac remodeling (5)(6)(7).…”