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1Division of Cardiology and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, California
Submitted 31 March 2005 ; accepted in final form 13 July 2005
ANG-(17) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(17) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(17) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. 125I-labeled ANG-(17) binding assays identified specific binding sites of ANG-(17) on adult rat cardiac fibroblasts (ARCFs) with an affinity of 11.3 nM and a density of 131 fmol/mg protein. At nanomolar concentrations, ANG-(17) interacted with specific sites that were distinct from ANG II type 1 and type 2 receptors without increasing cytosolic Ca2+ concentration. At these concentrations, ANG-(17) had inhibitory effects on collagen synthesis as assessed by [3H]proline incorporation and decreased mRNA expression of growth factors in ARCFs. These effects of ANG-(17) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(17) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(17) pretreatment also inhibited the stimulatory effects of conditioned medium from ANG II-treated ARCFs on [3H]leucine incorporation and atrial natriuretic factor mRNA expression, markers of hypertrophy, in cardiomyocytes. Thus ANG-(17) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(17) may play an important role in the heart in regulating cardiac remodeling.
angiotensin receptors; cardiac remodeling; renin-angiotensin system
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