Renin-Angiotensin System, Hypertrophy and Gene Expression in Cardiac Myocytes

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin (ANG ), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS on the myocyte protein synthesis (myocyte hypertrophy) and on the induction of gene expression will be discussed in rat cardiomyocytes in culture. The traditional RAS can be considered as a system in which circulating ANG is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of ANG can be mediated. These actions of ANG are primarily mediated through ANG receptors of the subtype (AT1-R). When evaluating the effects of ANG in situ, both changes in circulating levels and local production have to be taken into account. Discrepant findings on thein vitroeffect of ANG on the protein synthesis in cardiac myocytes are described and can be at least partly be attributed to methodological problems such as assay of thede novoprotein synthesis, isolation and the separation procedure of cardiac myocytes. The ANG -induced hypertrophic effect also depends on the existence of non-myocytes in a cardiocyte culture. In rat cardiocytes ANG also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletalα-actin and atrial natriuretic peptide expression) and growth factors (TGF-β1gene expression).In vivoANG via AT1-R, causes not only ventricular hypertrophy, independently of blood pressure, but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and ANG receptor antagonists of the subtype not only induce the regression, but also prevent the development of cardiac hypertrophy in experimental rat models.