Local stress, not systemic factors, regulate gene expression of the cardiac renin-angiotensin system in vivo: a comprehensive study of all its components in the dog.

Abstract

Local stress, not systemic factors, regulate gene expression of the cardiac renin-angiotensin system in vivo: A comprehensive study of all its components in the dog (heart/heart hypertrophy/gene regulation/heart failure) YOUNG-AE LEE*, CHANG-SENG LIANGt, MIN The renin-angiotensin system (RAS) contributes importantly to the maintenance of acute and chronic hemodynamic homeostasis by affecting the function as well as the structure of the cardiovascular system. In addition to the classically described endocrine (circulating) RAS, a number of organs and tissues have in recent years been found to express components of the RAS, leading to the concept of "local" or "tissueresident" RASs acting, presumably, via paracrine, autocrine, or intracrine pathways. The existence of an endogenous RAS in the heart has been confirmed by the demonstration of expression of the genes coding for angiotensinogen, renin (1), angiotensin converting enzyme (ACE), and angiotensin II receptors (2, 3), and by immunohistochemical demonstration of intracardiac angiotensin I and 11 (4). A second pathway for angiotensin II formation via a highly specific and potent serine protease, chymase, has recently been described in the human and canine heart (5, 6).Angiotensin II has been reported to modulate adaptive growth patterns in cardiac hypertrophy via autocrine or paracrine pathways. Angiotensin II stimulates protein synthesis in cardiomyocytes (7) and in cultured aortic vascular smooth muscle cells (8, 9), and appears to be required for the rapid growth of the neonatal heart (10). Upregulation of left ventricular angiotensinogen and ACE has been described in association with pressure-overload hypertrophy (11) and tachypacing-induced heart failure (12). ACE inhibitors are more effective in reversing or preventing cardiac hypertrophy associated with systemic hypertensive states (13, 14) than other agents with equal hypotensive effects (15). Recent in vitro data indicate that activation of the cardiomyocyte RAS is induced by mechanical stress, and that angiotensin II is an essential mediator of stretch-induced cardiac myocyte hypertrophy (16). So far, no corresponding information assessing the role of mechanical stress versus that -of circulating soluble factors in modulating RAS expression in vivo has been presented. Also, a comprehensive assessment of cardiac RAS gene expression in vivo and in vitro has been precluded because no study so far has examined all components of the cardiac RAS. Thus, the goals of the present work were to study the possible role of local mechanical versus systemic soluble factors in the modulation of cardiac RAS gene expression, and to conduct a comprehensive assessment of cardiac gene expression of all known components of the RAS. We studied a canine model of combined pressure-and volume-overload-induced right ventricular hypertrophy and failure (RVHF). In contrast to left ventricular failure, which invariably also results in some hemodynamic embarrassment and, thus, mechanical stress of the right ventricle (RV) transmit...

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation

“…75,76 Fibrosis is also triggered by atrial dilation in any type of heart disease associated with AF, including valvular disease, hypertension, HF, or coronary atherosclerosis. 77 Stretch activates several molecular pathways, including the renin-angiotensin-aldosterone system (RAAS). Both angiotensin II and transforming growth factor-beta1 (TGF-beta1) are upregulated in response to stretch, and these molecules induce production of connective tissue growth factor (CTGF).…”

An analysis of the effects of stretch on IGF-I secretion from rat ventricular fibroblasts

“…Responses to applied or intrinsic mechanical forces have been studied in many cell types. Well-established stretch-mediated responses include gene expression regulation (39), cell proliferation ( 48 ), and peptide growth factor induction (25,46). Using a static stretch system, van Wamel et al (46) showed that stretch could cause neonatal CFb to release TGF-␤1.…”

Cardiac Growth Factors in Human Hypertrophy

“…Evidence has been provided both in vitro and in vivo that mechanical forces can selectively regulate gene expression and cause differential induction of peptide growth factors. [27][28][29] The augmented formation of IGF-I and ET-1 depends on the increased left ventricle load and is not related to possible derangements of pulmonary or peripheral hemodynamics, because no evidence of enhanced cardiac growth factor formation was found in patients with mitral stenosis despite the presence of atrial fibrillation, enhanced pulmonary arterial pressure, and increased levels of circulating ET-1 and Big ET. Likewise, the occurrence of stable effort angina in the formation of ET-1 and IGF-I seems to play a minor role, given that no significant differences were found between patients with and patients without angina and coronary artery disease.…”