Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage

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 (AM +/-) 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-beta, 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 AM +/- 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 AM +/- 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 AM +/- 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 C and protein kinase A - dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.