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

Abstract

Abstract-In this study we investigated the effects of the genetic deletion of the angiotensin (Ang)-(1-7) receptor Mas on heart function. Localization of Mas in the mouse heart was evaluated by binding of rhodamine-labeled Ang-(1-7). Cardiac function was examined using isolated heart preparations. Echocardiography was used to confirm the results obtained with isolated heart studies. To elucidate the possible mechanisms involved in the cardiac phenotype observed in Mas Ϫ/Ϫ mice, whole-cell calcium currents in cardiomyocytes and the expression of collagen types I, III, and VI and fibronectin were analyzed. Ang-(1-7) binding showed that Mas is localized in cardiomyocytes of the mouse heart. Isolated heart techniques revealed that Mas-deficient mice present a lower systolic tension (average: 1.4Ϯ0.09 versus 2.1Ϯ0.03 g in Mas ϩ/ϩ mice), ϮdT/dt, and heart rate. A significantly higher coronary vessel resistance was also observed in Mas-deficient mice. Echocardiography revealed that hearts of Mas-deficient mice showed a significantly decreased fractional shortening, posterior wall thickness in systole and left ventricle end-diastolic dimension, and a higher left ventricle end-systolic dimension. A markedly lower global ventricular function, as defined by a higher myocardial performance index, was observed. A higher delayed time to the peak of calcium current was also observed. The changes in cardiac function could be partially explained by a marked change in collagen expression to a profibrotic profile in Mas-deficient mice. These results indicate that Ang-(1-7)-Mas axis plays a key role in the maintenance of the structure and function of the heart. (Hypertension. 2006;47:996-1002.)

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In agreement with the activities that were previously described for ANG-(1-7), Mas-deficient mice exhibited increased blood pressure, impaired endothelial function, decreased NO production, and decreased endothelial NO synthase expression [138,139]. Also in agreement with findings showing the cardioprotective effects of ANG-(1-7), a genetic deletion of the Mas receptor impaired heart function and changed the extracellular matrix to a profibrotic state [140]. After the activation of the Mas receptor, the intracellular signal transduction mechanisms that are involved in the following processes or tissues are poorly understood: i) in vivo, in the rat heart, ANG-(1-7) stimulated the phosphorylation of Janus kinase 2 (JAK2), insulin receptor substrate (IRS)-1 and Akt [141], ii) Mas receptor activation led to an increase in NO production via the phosphorylation of eNOS, a process that involves the activation of phosphatidylinositol 3-kinase-dependent Akt phosphorylation [142,143], and iii) upon the activation of the Mas receptor, MAPK phosphorylation is inhibited [144,145].…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…Ang-(1-7) is also formed in human hearts and ACE inhibitors markedly decrease Ang-(1-7) generation, suggesting a substrate preference for Ang II (Zisman et al 2003) although contrasting evidence has also been presented (Campbell et al 2004), which may be due to the different tissue preparations (homogenates or coronary bed) used in both studies. Of note, the Ang-(1-7) receptor Mas, mRNA and protein (Metzger et al 1995, Santos et al 2006, is localized in cardiac tissues as well as ACE2, the main Ang-(1-7)-forming enzyme utilizing Ang II as substrate (Harmer et al 2002, Garabelli et al 2008.…”

“…However, the role of Ang-(1-7) is not limited to its counterregulatory action. Indeed, genetic deletion of Mas produces an extremely rich phenotype which includes cardiac dysfunction (Santos et al 2006), increased blood pressure (genetic background dependent) , decreased baroreflex function (de Moura et al 2010), endothelial dysfunction , reduced reproductive function, increased thrombogenesis (Fraga-Silva et al 2008) and, depending on genetic background, marked changes in lipid and glucose metabolism leading to a metabolic syndrome like state (Santos et al 2006;Fig. 3).…”

Angiotensin (1−7) prevent heart dysfunction and left ventricular remodeling caused by renal dysfunction in 5/6 nephrectomy mice

“…This phenomenon reflects a ligand-dependent autoinduction of Mas gene expression, similar to the situation that has been reported for hepatocyte growth factor (HGF) and c-Met/HGF receptor. 37 Recently, Santos et al 38 found that genetic deletion of the Mas receptor caused significantly deleterious effects on cardiac function and structure, particularly with regard to myocardial fibrosis, which suggests that Mas is necessary for Ang-(1-7) transduction. However, the exact mechanism through which Ang (1-7) increased the Mas expression has not been elucidated yet.…”