Role of Renin-Angiotensin System in Cardiac Hypertrophy and Failure

Abstract

Although the circulatory renin-angiotensin system (RAS) was discovered a century ago, it is only recently that the presence of tissue RAS has become evident. Angiotensin (Ang) II has been demonstrated to influence heart function by effecting cardiac contraction, myocyte growth, cardiac matrix, and cardiac metabolism. These actions are initiated by the binding of Ang II to plasma membrane receptors, namely, AT1 and possibly AT2, which stimulates phospholipase C (PLC) to produce phosphatidylinositol 4,5-bisphosphate, thus forming diacylgjycerol (DAG) and inositol 1,4,5-triphosphate (IP3). An increase in the intracellular Ca2+ appears to result from IP3-mediated release of Ca2+ from the intracellular stores, and this effect may be associated with an increase in cardiac force development. On the other hand, DAG activates protein kinase C (PKC) which stimulates cardiac growth and other actions of Ang II. Intracellular signaling of Ang II-stimulated cardiomyocyte growth may include the activation of tyrosine kinase and mitogen-activated protein kinase (MAPK) cascade. Alterations in different components of RAS, such as renin, angiotensinogen, and angiotensin-converting enzyme (ACE), as well as Ang II receptors (AT1 and AT2), have been shown to occur in different pathological conditions of cardiac hypertrophy and heart failure. On the other hand, ACE genotype has been shown to exhibit a close relationship with myocardial infarction. In this article, we have attempted to review the influence of ACE inhibitors on different types of cardiac hypertrophy and heart failure. Although existing results are controversial, ACE inhibitors, in general, have been shown to exert beneficial effects on cardiac function in myocardial infarction, cardiac hypertrophy from volume or pressure overload, as well as heart failure because of pacing and cardiomyopathy. The possible mechanisms of the effects of ACE inhibitors may include reduction in both circulating and local RAS, scavenging of free radicals, improvement of energy metabolism, modification of the autonomic nervous system, and increase of bradykinin concentration. More importantly, ACE inhibitors may improve cardiac function by remodeling the cell membranes, mobilizing Ca2+, and attenuating the shift in myosin isozymes. Although Ang II receptor antagonists have also been shown to have protective effects on contractile function in cardiac hypertrophy and heart failure, the mechanisms remain to be fully understood.