Angiotensin-(1–7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1

Abstract

Chronic hypertension induces cardiac remodeling, including left ventricular hypertrophy and fibrosis, through a combination of both hemodynamic and humoral factors. In previous studies, we showed that the heptapeptide ANG-(1-7) prevented mitogen-stimulated growth of cardiac myocytes in vitro, through a reduction in the activity of the MAPKs ERK1 and ERK2. In this study, saline- or ANG II-infused rats were treated with ANG-(1-7) to determine whether the heptapeptide reduces myocyte hypertrophy in vivo and to identify the signaling pathways involved in the process. ANG II infusion into normotensive rats elevated systolic blood pressure >50 mmHg, in association with increased myocyte cross-sectional area, ventricular atrial natriuretic peptide mRNA, and ventricular brain natriuretric peptide mRNA. Although infusion with ANG-(1-7) had no effect on the ANG II-stimulated elevation in blood pressure, the heptapeptide hormone significantly reduced the ANG II-mediated increase in myocyte cross-sectional area, interstitial fibrosis, and natriuretic peptide mRNAs. ANG II increased phospho-ERK1 and phospho-ERK2, whereas cotreatment with ANG-(1-7) reduced the phosphorylation of both MAPKs. Neither ANG II nor ANG-(1-7) altered the ERK1/2 MAPK kinase MEK1/2. However, ANG-(1-7) infusion, with or without ANG II, increased the MAPK phosphatase dual-specificity phosphatase (DUSP)-1; in contrast, treatment with ANG II had no effect on DUSP-1, suggesting that ANG-(1-7) upregulates DUSP-1 to reduce ANG II-stimulated ERK activation. These results indicate that ANG-(1-7) attenuates cardiac remodeling associated with a chronic elevation in blood pressure and upregulation of a MAPK phosphatase and may be cardioprotective in patients with hypertension.

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…A similar action was described for AVE0991 (Sheng-Long et al, 2012). This feature appears not to be restricted to VSMC, considering that Ang-(1-7) has well documented antiproliferative effects in other cell types, including cardiac fibroblasts (McCollum et al, 2012) and tumoral cells (Gallagher and Tallant, 2004;Ni et al, 2012). The involvement of Mas in these Ang-(1-7) effects was supported by the use of the Mas antagonist A-779.…”

“…Accordingly, He et al (2004), and later on many other investigators (Iwata et al, 2005;Tallant et al, 2005;Grobe et al, 2006;Iusuf et al, 2008;Mercure et al, 2008;Li et al, 2009;Giani et al, 2010;Gomes et al, 2010;Pei et al, 2010;Varagic et al, 2010;Iwata et al, 2011;Durik et al, 2012;McCollum et al, 2012;Patel et al, 2012;Zeng et al, 2012;de Almeida et al, 2013), described antiremodeling effects of Ang-(1-7) and of other Mas agonists (AVE 0991/CGEN-856S) (Ferreira et al, 2007;Savergnini et al, 2010). These observations are in line with the deleterious cardiac effects of genetic ablation of Mas in mice (Santos et al, 2006;Gava et al, 2012).…”

“…Most of the data related to Mas and its ligand Ang-(1-7) in the heart have shown cardioprotective effects of Ang-(1-7) (Ferreira et al, 2001(Ferreira et al, , 2007Santos et al, 2004;Iwata et al, 2005Iwata et al, , 2011Tallant et al, 2005;Grobe et al, 2006;Iusuf et al, 2008;Mercure et al, 2008;Li et al, 2009;Giani et al, 2010;Gomes et al, 2010;Pei et al, 2010;Santiago et al, 2010;Varagic et al, 2010;Marques et al, 2011Marques et al, , 2012Qi et al, 2011;Durik et al, 2012;McCollum et al, 2012;Patel et al, 2012;Zeng et al, 2012;Cunha et al, 2013;de Almeida et al, 2013) with only one exception .…”

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

“…Consistent with this, further in vivo studies using genetically engineered mice also found that ACE3 provides protective effects against chronic pressure overload‐induced cardiac hypertrophy, fibrosis, and dysfunction. Accumulating evidence has pointed out that ACE2 and its primary product Ang 1 to 7 play critical roles in the pathophysiology of cardiovascular disease, especially the protective actions against pathological cardiac hypertrophy 20, 21. We demonstrated that ACE3, as a new component of the ACE family, has the ability to impair Ang II‐ and pressure overload‐induced cardiac hypertrophy in this study.…”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…After the identification of MasR as the main receptor for Ang-(1-7) [92], the protective role of Ang-(1-7)/MasR axis has been shown in endothelial dysfunction [119], global ischemia [120], ischemia/reperfusion (I/R) [116], MI [121], cardiac remodeling [122] and HF [123]. It is widely known that I/R induces arrhythmias and contractile dysfunction in cardiac cells and that Ang-(1-7) has a cardioprotective role.…”