Inhibition of Catecholamine-Induced Cardiac Fibrosis by an Aldosterone Antagonist

Abstract

In heart failure, the renin-angiotensin-aldosterone and the sympathetic systems are overactivated and lead to formation of cardiac fibrosis, which contributes to the aggravation of cardiac function. The aim of the present study was to evaluate the role of aldosterone and angiotensin II on formation of left ventricular fibrosis induced by chronic beta-adrenergic stimulation with isoproterenol (iso) in the rat heart failure model induced by myocardial infarction (MI). Rats were submitted to chronic treatment with either the aldosterone receptor antagonist potassium canrenoate (pc, 20 mg/kg/d) or both aldosterone and angiotensin II receptor antagonists with addition of losartan (los, 10 mg/kg/d). Isoproterenol induced cardiac hypertrophy, which was completely inhibited by potassium canrenoate alone in atria and by potassium canrenoate plus losartan in infarcted ventricles. Isoproterenol also induced cardiac fibrosis, which was completely inhibited in infarcted rats by potassium canrenoate alone in right and left ventricles. In left ventricle, extent of fibrosis was, for control MI, 1.30 +/- 0.34%; MI + iso, 2.50 +/- 0.27%; MI + iso + pc, 0.82 +/- 0.11%; and MI + iso + pc + los, 1.47 +/- 0.31%. The deleterious effects of beta-adrenoceptor stimulation on cardiac fibrosis seem therefore to involve aldosterone action. These results suggest a transregulation between the adrenergic and mineralocorticoid pathways, most likely at the nucleus level, with activation of profibrotic genes.

β1 Integrins Modulate β-Adrenergic Receptor–Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling

“…7 MMPs play an important role in the remodeling of ECM. 36 Of these, expression of MMP-2 is of particular interest, because MMP-2 degrades ECM substrates including type IV collagen, laminin, elastin, and interstitial fibrillar collagen.…”

“…1,2 Excessive ␤-adrenergic receptor (␤-AR) stimulation induces cardiac myocyte apoptosis in vivo and in vitro and cardiac chamber remodeling associated with hypertrophy and/or fibrosis. [3][4][5][6][7] Integrins, a family of ␣␤-heterodimeric cell surface receptors, link the extracellular matrix (ECM) proteins and the intracellular cytoskeleton. Integrins are demonstrated to play an important role in the regulation of various genes related to cell growth, apoptosis, and hypertrophy.…”

Pathophysiological and Clinical Approach to Cirrhotic Cardiomyopathy

“…Aldosterone may have various harmful effects on the myocardium and the cardiovascular system [16]. Consequently, mineralocorticoid receptor antagonists may be among the first choices of therapy [84]. They can improve the hemodynamic properties of patients with cirrhosis and may decrease the severe symptoms of heart failure [85].…”

Efficacy and safety of mineralocorticoid receptor antagonist therapy in heart failure with reduced ejection fraction

“…The mechanism of how MRAs decrease mortality in HFrEF is unknown; however, it likely extends beyond the blocking of aldosterone-mediated retention of sodium and water. In (12)(13)(14)(15). These agents have also been associated with improved endothelial function and increased nitric oxide bioactivity in HF patients (15,16).…”