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The first evidence in supporting the hypothesis
The first evidence in supporting the hypothesis that MAS receptors mediate the effects elicited by AT1 antagonists was provided by Iwai et al. (2012). The authors found that AT1 receptors triggers neointima formation after polyethylene-cuff placement around mouse femoral artery by reducing local ACE2 gene expression and the local levels of angiotensin-(1-7), which impairs the local MAS-mediated counterregulation of AT1-dependent proliferative actions on VSMC. According to their findings, olmesartan (AT1 antagonist) treatment inhibited neointima formation by recovering local ACE2 and angiotensin-(1-7) levels. Moreover, [d-Ala(7)]-angiotensin-(1-7) (MAS antagonist) co-treatment blunted the inhibitory effects of olmesartan on the vascular remodeling, suggesting that MAS receptors are involved in the vasoprotective effects of AT1 antagonists (Iwai et al., 2012). Corroborating with the findings from Iwai et al. (2012), Ohshima et al. (2014) also found that azilsartan (AT1 antagonist) elicited sustained inhibitory effects on neointima formation induced by polyethylene-cuff placement around mouse femoral artery by reducing the local inflammation, oxidative stress and VSMC proliferation. However, the inhibitory effects on vascular remodeling promoted by azilsartan treatment were almost blunted in MAS deficient mice, suggesting that MAS receptors mediate the vasoprotective effects of AT1 antagonists (Ohshima et al., 2014). The authors also observed that angiotensin-(1-7) treatment also reduced the neointimal area similarly to azilsartan. Interestingly, angiotensin-(1-7) treatment elicited a residual inhibitory effect on vascular remodeling in MAS deficient mice, suggesting that another receptor than MAS prmt5 inhibitor would be mediating such small extent from the vasoprotective action. This effect was attenuated in AT2 deficient mice, pointing that AT2 receptors mediate part of the vasoprotective effect elicited by angiotensin-(1-7) (Ohshima et al., 2014). In fact, the heptapeptide exhibits a discrete affinity towards AT2 binding sites (Bosnyak et al., 2011), which allowed Ohshima et al. (2014) to propose a putative discrete role to angiotensin-(1-7)-activated AT2 receptors as a second final mediator of the vasoprotective effects elicited by AT1 antagonists beyond MAS receptors. Later, Pernomian et al. (2015) found that MAS receptors also mediate the vasoprotective and atheroprotective effects of candesartan (AT1 antagonist) upon the recovery of the functionality of vascular ACE2–angiotensin-(1-7)–MAS axis in the early stages of atherosclerosis. According to the authors, the initial step of the atherogenic process impairs ACE2 activity in generating angiotensin-(1-7) and MAS-mediated nitrergic relaxation in mouse thoracic aorta by an AT1-mediated redox-proinflammatory signaling involving the tumor necrosis factor-α (TNF-α)-activated Nox1-driven generation of superoxide () and H2O2. Candesartan treatment restored the local ACE2–angiotensin-(1-7)–MAS axis functionality and promoted vasoprotective and atheroprotective effects by recovering the local endothelial function and elastin and type I collagen deposition. Interestingly, the vasoprotective and atheroprotective effects of candesartan were blunted by the co-treatment with A779 (MAS antagonist), confirming that MAS receptors are the final mediators of such effects (Pernomian et al., 2015). Besides cardiovascular protective effects, MAS receptors also seem to mediate other actions elicited by AT1 antagonists. Schuchard et al. (2015) recently showed that the anti-obesity (weight loss) effects promoted by telmisartan (AT1 antagonist) in diet-induced obese rats were partially inhibited by the MAS antagonist A779 by impairing cellular glucose uptake. Taken together, the findings from Iwai et al. (2012), Ohshima et al. (2014), Pernomian et al. (2015) and Schuchard et al. (2015) strongly support the evidence that the pharmacological antagonism on AT1 receptors enhances the functionality of ACE2–angiotensin-(1-7)–MAS axis and makes MAS receptors the putative final mediators of important effects triggered by AT1 antagonists. Such mechanism highlights the significance of the interplay between AT1 and MAS receptors to RAS Pharmacology.