Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

Abstract

Background-Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function.The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice. Methods and Results-Mice heterozygous for an AM-null mutation (AMϩ/Ϫ) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-␤, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AMϩ/Ϫ mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AMϩ/Ϫ mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AMϩ/Ϫ myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway. Conclusions-Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase Cand protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

“…29,30 Heterozygous adrenomedullin-deficient mice exhibit more severe cardiac and renal damage in mouse models of angiotensin II infusion and transverse aortic constriction. 31,32 However, neither BNP nor adrenomedullin has been evaluated for their effects on kidney function using genetic models that specifically ablate their expression in heart. Here, we show that cardiac myocyte-specific ablation of Fstl1 exacerbates kidney damage after subtotal nephrectomy, indicating the importance of Fstl1 as a cardiokine with renal protective properties.…”

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

“…Ang II is profibrotic for CFs from multiple species, including those isolated from explanted human hearts (2,42). Gene delivery of adrenomedullin attenuates cardiac and renal fibrosis in deoxycorticosterone acetate-salt-hypertensive rats (43), and adrenomedullinknockout mice exhibit increased fibrosis and elevated expression of TGF-␤ in both heart and kidney (44). Unlike previous studies (15) that used CFs isolated from neonatal rats, in our studies with adult rats, we did not observe an inhibition of collagen synthesis unless we overexpressed AC6 (compare Figs.…”

Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System

“…11 On the other hand, heterozygotic AM knockout (AM±) mice were apparently normal, although they exhibited higher blood pressure and cardiac hypertrophy when subjected to cardiovascular stress. 6,12 Conversely, transgenic mice overexpressing AM have shown lower blood pressure and resistance to various forms of organ damage, 13,14 suggesting that AM exerts organ protective as well as hypotensive effects. [15][16][17][18] The AM receptor calcitonin receptor-like receptor is a 7-transmembrane domain G protein-coupled receptor ) is lethal in utero and reproduces the phenotypes observed in AM −/− mice.…”