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.

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Abstract-Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an important determinant of cardiac function. Tumor necrosis factor-␣ (TNF-␣) and angiotensin (Ang) II levels increase after MI and both factors affect fibroblast functions. The type 1 (AT 1 ) receptor that mediates most Ang II effects is upregulated after MI in cardiac fibroblasts, and there is evidence that this is caused by TNF-␣. We sought to determine if TNF-␣-induced AT 1 receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF-␣ effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF-␣ reduced cellular [ 3 H]-proline incorporation, increased matrix metalloproteinase-2 (MMP-2) activity and protein, and increased TIMP-1 protein levels. In cardiac fibroblasts with TNF-␣-induced AT 1 receptor upregulation, Ang II-stimulated [ 3 H]proline incorporation and TIMP-1 protein production was approximately 2-fold greater than in nonpretreated fibroblasts. Angiotensin II reduced MMP-2 activity and protein level only in TNF-␣-pretreated fibroblasts. Angiotensin II effects were inhibited by selective AT 1 (but not AT 2 ) receptor blockers. Thus, TNF-␣-induced AT 1 receptor upregulation enhances Ang II-mediated functions that favor fibrosis. These effects are mostly directionally opposite of direct TNF-␣ effects on cardiac fibroblasts. Key Words: collagen synthesis Ⅲ tumor necrosis factor-␣ Ⅲ matrix metalloproteinase Ⅲ tissue inhibitor of matrix metalloproteinase Ⅲ angiotensin II P ost-myocardial infarction (MI) remodeling is a complex process involving biochemical, structural, and geometric changes in the heart. The resulting alterations in ventricular size and shape are an important cause of heart failure. Although alterations in myocyte structure and function clearly play a role in remodeling, fibroblast effects on the extracellular matrix (ECM) contribute significantly to the remodeling process. 1 ECM remodeling involves tissue breakdown and formation of the replacement scar at the infarct site. Progressive accumulation of fibrous tissue including reactive perivascular/interstitial fibrosis and reparative fibrosis in response to myocyte loss also occurs in noninfarcted segments of myocardium. 1-3 Both the adequacy of replacement scar formation and the extent of fibrosis in noninfarcted myocardium are determinants of systolic and diastolic function of the heart. 4,5 Thus, better understanding of factors that influence fibroblast function during ECM remodeling should provide important insights into the pathogenesis of heart failure.After MI there is initial tissue breakdown at the infarct site followed by ECM deposition in this region and in noninfarcted myocardium. [1][2][3][4][5][6] Collagen breakdown involves the activation of degradative enzymes termed matrix metalloproteinases (MMPs). 7 These endogenous zinc-dependent enzymes are regulated by proteins known as tissue inhibitors of metalloproteinases (TIMPs). Cardiac fibroblasts and phenotypically transform...

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