The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

Abstract

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

Candesartan-Induced Gene Expression in Five Organs of Stroke-Prone Spontaneously Hypertensive Rats

“…The RAS components are locally expressed in the heart and capable of generating Ang II. It is known that the cardiac RAS is involved in the induction of hypertrophy, fibrosis and remodeling and is therefore of significant clinical relevance to the study of hypertension and heart failure (4)(5)(6)18). Our observation that candesartan induces a prominent alteration in cardiac gene expression strengthens the general understanding that locally generated angiotensin peptides have multiple and novel diverse actions, including cell growth, cell proliferation and cell death (5).…”

“…Accordingly, tissue concentrations of angiotensin II (Ang II), other RAS compo-nents and their active metabolites can be set independently of the circulatory RAS and may either potentiate systemic functions or have entirely separate activities to meet the specific needs of individual tissues (5). Accumulating evidence indicates that impairments in the local RAS underlie certain tissue/organ disorders such as stroke and heart failure (3,4,6). This gives rise to the possibility that a class of drugs that act on the local RAS may effectively ameliorate some of these disorders.…”

Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function

“…In fact, we and others have demonstrated that genetic and nongenetic animal models of neurohumoral overactivation result in remarkable maladaptive cardiac remodeling associated with ventricular dysfunction (3,4). This concept is supported by findings from HF animal models and clinical trials showing that inhibition or regression of cardiac hypertrophy by drugs targeting neurohumoral systems (i.e., ACE inhibitors and β-blockers) lowers the risk for death and HF development (4,9). Over the last few years, our group has reported that exercise training strikingly counteracts the deleterious effects of neurohumoral overactivation in HF.…”

“…The development of HF involves a continuous interaction between myocardial dysfunction and a compensatory activation of neurohumoral systems such as sympathetic and renin-angiotensin-aldosterone hyperactivity to name a few (2). At first, this response is compensatory, but sustained neurohumoral hyperactivity is toxic (3,4) and portends a poor prognosis (5). HF treatment aims to improve prognosis and control symptoms by blocking neurohumoral hyperactivity with the use of β-adrenoceptor blockers, inhibitors of angiotensin-converting enzyme (ACE), angiotensin II receptor blockers and inhibitors of aldosterone synthesis, and by controlling fluid retention (6).…”

“…HF treatment aims to improve prognosis and control symptoms by blocking neurohumoral hyperactivity with the use of β-adrenoceptor blockers, inhibitors of angiotensin-converting enzyme (ACE), angiotensin II receptor blockers and inhibitors of aldosterone synthesis, and by controlling fluid retention (6). Even though neurohumoral blockade is associated with a better prognosis (7), reversal remodeling (4,8,9) and improved cardiac calcium handling (9), HF remains a major cause of illness and death. Thus, new strategies for HF treatment and prevention are among the great challenges facing health sciences today.…”