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Am J Physiol Heart Circ Physiol 289: H2356-H2363, 2005. First published July 15, 2005; doi:10.1152/ajpheart.00317.2005
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Angiotensin-(1–7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects

Michikado Iwata,1 Randy T. Cowling,1 Devorah Gurantz,1 Cristina Moore,1 Shen Zhang,2 Jason X.-J. Yuan,2 and Barry H. Greenberg1

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-(1–7) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(1–7) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(1–7) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. 125I-labeled ANG-(1–7) binding assays identified specific binding sites of ANG-(1–7) 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-(1–7) 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-(1–7) 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-(1–7) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(1–7) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(1–7) 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-(1–7) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(1–7) may play an important role in the heart in regulating cardiac remodeling.

angiotensin receptors; cardiac remodeling; renin-angiotensin system



Address for reprint requests and other correspondence: B. Greenberg, Dept. of Medicine/Cardiology, UCSD Medical Center, 200 West Arbor Dr., San Diego, CA 92103-8411 (e-mail: bgreenberg{at}ucsd.edu)




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