Abstract-Recently there has been growing evidence suggesting that beneficial effects of angiotensin-(1-7) ] in the heart are mediated by its receptor Mas. However, the signaling pathways involved in these effects in cardiomyocytes are unknown. Here, we investigated the involvement of the Ang-(1-7)/Mas axis in NO generation and Ca 2ϩ handling in adult ventricular myocytes using a combination of molecular biology, intracellular Ca 2ϩ imaging, and confocal microscopy. Acute Ang-(1-7) treatment (10 nmol/L) leads to NO production and activates endothelial NO synthase and Akt in cardiomyocytes. Ang-(1-7)-dependent NO raise was abolished by pretreatment with A-779 (1 mol/L). To confirm that Ang-(1-7) action is mediated by Mas, we used cardiomyocytes isolated from Mas-deficient mice. In Mas-deficient cardiomyocytes, Ang-(1-7) failed to increase NO levels. Moreover, Mas-ablation was accompanied by significant alterations in the proteins involved in the regulation of endothelial NO synthase activity, indicating that endothelial NO synthase and its binding partners are important effectors of the Mas-mediated pathway in cardiomyocytes. We then investigated the role of the Ang- (1-7)

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These results indicate that Ang-(1-7) has blood pressure-independent, antifibrotic effects, acting directly in the heart.

Heart failure patients with preserved left ventricular ejection fraction (HFpEF) have endothelial dysfunction, but the underlying molecular mechanisms remain unknown. In addition, whether exercise training improves endothelial function in HFpEF is still controversial. The present study therefore aimed to determine the functional and molecular alterations in the endothelium associated with HFpEF, while further assessing the effects of high-intensity interval training (HIT). Female Dahl salt-sensitive rats were randomized for 28 wk into the following groups: 1) control: fed 0.3% NaCl; 2) HFpEF: fed 8% NaCl; and 3) HFpEF + HIT: animals fed 8% NaCl and HIT treadmill exercise. Echocardiography and invasive hemodynamic measurements were used to assess diastolic dysfunction. Endothelial function of the aorta was measured in vitro. Expression of endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase [NAD(P)H oxidase], and advanced glycation end product (AGE)-modified proteins were quantified by Western blot, and zymography quantified matrix metalloproteinase (MMP) activity. In this model of HFpEF, endothelium-dependent and -independent vasodilation was impaired. However, this was prevented by HIT. In HFpEF protein expression of eNOS was reduced by 47%, but MMP-2 and MMP-9 activity was elevated by 186 and 68%. The expression of AGE-modified proteins was increased by 106%. All of these changes were prevented by HIT. Endothelial function was impaired in this model of HFpEF, which was associated with reduced expression of eNOS, increased MMP activity, and increased AGE-modified proteins. HIT was able to attenuate both these functional and molecular alterations. These findings therefore suggest HFpEF induces endothelial dysfunction, but this is reversible by HIT.