Angiotensin-(1–7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects

Abstract

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.

Impairment of In Vitro and In Vivo Heart Function in Angiotensin-(1-7) Receptor Mas Knockout Mice

“…The fact that collagen VI undergoes an opposite change as that observed for collagen I, III, and fibronectin suggests that this influence is selective. These observations are in accordance with a recent report by Iwata et al, 17 showing that Ang-(1-7) produces antifibrotic effects. As expected, 24,27 a contribution of BP to the changes in collagen expression or in cardiac function could be excluded by the direct BP measurements in halothane-anesthetized and in nonanesthetized mice.…”

“…36 More recently, it has been demonstrated in humans that treatment with aldosterone antagonists substantially increased ACE2 activity. 38 The prominent decrease in cardiac function in Mas Ϫ/Ϫ mice, which can be correlated with the marked changes in extracellular matrix proteins and the antihypertrophic effects of Ang-(1-7), 16,17 apparently mediated by its interaction with Mas, 18 suggest that activation of the Ang-(1-7)-forming pathways by RAS blockade produces beneficial cardiac effects through activation of Mas. One could argue that ACE2 knockout mice 39 showed more pronounced cardiac function impairment than Mas knockout mice.…”

“…21,22 In rodents, Mas mRNA has been detected in the heart in addition to other tissues, such as testis, kidney, and brain. 23 Recent in vitro studies have suggested that Ang-(1-7) induces antifibrotic and antitrophic effects in cardiac cells when it binds to cardiac fibroblasts 17 and reduces the growth of cardiomyocytes through activation of the Mas receptor. 18 However, there are little data available concerning the potential role of Mas in the heart.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…Indeed, chronic Ang-(1-7) treatment not only attenuated the development of heart failure in response to coronary artery ligation in rats (Loot et al 2002), but it also reversed cardiac hypertrophy and fibrosis in rats (Iwata et al 2005;Tallant et al 2005;Wang et al 2005;Grobe et al 2006a;2006b). Ishiyama et al (2004) found that heart failure induced by coronary artery ligation was associated with an increase in plasma Ang-(1-7) levels, which was augmented with the administration of the AT 1 receptor blockers losartan and olmesartan.…”

Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

“…1). These include antihypertensive, antiarrhythmic, cardioprotective anti-inflammatory, anti-fibrotic, anti-thrombotic and antitrophic effects in a number of different cell types (Benter et al 1995;Ferreira et al 2001Ferreira et al , 2002Freeman et al 1996;Grobe et al 2006;Iwata et al 2005;Kucharewicz et al 2000Kucharewicz et al , 2002Strawn et al 1999;Tallant et al 2005). Ang-(1-7) is degraded by ACE into the inactive peptide Ang-(1-5).…”