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    • Recent studies have supported the existence of an inward RAS

    2023-01-16

    Recent studies have supported the existence of an inward RAS regulatory mechanism in which AT1 receptors downregulate angiotensin-converting enzyme 2 (ACE2) and subsequently impair angiotensin-(1-7) generation and MAS functionality (Jessup et al., 2006, Gallagher et al., 2008, Xia et al., 2009, Pernomian et al., 2014b, Deshotels et al., 2014). The first evidences of this mechanism were based on the findings that losartan (AT1 antagonist) treatment increased ACE2 activity and gene expression in rat cardiac and renal tissues (Jessup et al., 2006) or mouse rosmarinic acid (Xia et al., 2009) while angiotensin II-induced AT1 activation reduced ACE2 gene expression in rat fibroblasts and cardiomyocytes (Gallagher et al., 2008). Later, Pernomian et al. (2014b) showed that AT1 receptors downregulate ACE2 activity in generating angiotensin-(1-7) from angiotensin II upon the activation of swelling-induced chloride currents (ICl,SWELL) mediated by hydrogen peroxide (H2O2) derived from AT1-stimulated NAD(P)H oxidase. The inhibitory effect of ICl,SWELL activation on ACE2 activity is possible due to existence of a regulatory chloride (Cl−) binding site at ACE2 extracellular domain (Towler et al., 2004), which inhibits the cleavage of angiotensin II by ACE2 (Rushworth et al., 2008). This regulatory site is activated upon the increase in Cl− extracellular levels, which results from ICl,SWELL activation by H2O2 derived from AT1-activated NAD(P)H oxidase (Ren et al., 2008, Matsuda et al., 2010). Beyond the molecular mechanism underlying AT1-mediated inhibition of ACE2 activity, the cellular pathway involved in the inhibitory effects played by AT1-receptors on ACE2 expression was also elucidated. Angiotensin II blunts the transcriptional regulation of ACE2 by a p38 mitogen-activated protein kinase (MAPK)- and ERK1/2-mediated mechanism upon AT1 activation (Xiao et al., 2013). Furthermore, angiotensin II-induced AT1 activation triggers a post-translational regulation of ACE2 by inducing its internalization and protease degradation in cytosolic lysosomes upon ubiquination after AT1-mediated inhibition of ACE2 activity (Deshotels et al. 2014). In brief, the evidences described above point that the interplay between AT1 and MAS receptors relies on the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of ACE2. These mechanisms are summarized in Fig. 1.
    Inotropic and redox-proinflammatory signaling underlying AT1 activation makes AT1 receptors the main mediators of the pathophysiological events underlying several diseases specially those affecting cardiovascular system (arterial hypertension, atherosclerosis, stroke, heart failure, infarction) (Iwai and Horiuchi, 2009). The pivotal pathophysiological role assigned to AT1 receptors spurred the clinical interest in using AT1 antagonists as the first therapeutic choice for preventing or attenuating cardiovascular damages. Indeed, the randomized controlled multicenter studies LAARS (Losartan Vascular Regression Study) (Ludwig et al., 2002) and MITEC (Media Intima Thickness Evaluation with Candesartan Cilexetil) (Baguet et al., 2009) have confirmed the efficacy of AT1 antagonists (losartan 50mg/day during 2 years in LAARS; candesartan 8mg/day during 3 years in MITEC) in reducing carotid intima-media thickness (IMT) in normoglycaemic or type 2-diabetic hypertensive patients, respectively. Increased carotid IMT is a classic marker of carotid and coronary atherosclerosis so that the inhibitory effects on this kind of remodeling imply atheroprotective, vasoprotective and cardioprotective efficacy to the AT1 antagonists (Sonoda et al., 2008). In view of the regulatory mechanisms involved in the interplay between AT1 and MAS receptors, recent studies have strongly supported the hypothesis that MAS receptors are putative final mediators of the cardiovascular effects triggered by AT1 antagonists (Iwai et al., 2012, Ohshima et al., 2014, Pernomian et al., 2015) since angiotensin-(1-7) evokes MAS-dependent cardioprotective, vasoprotective and atheroprotective actions (Santos et al., 2013). Indeed, the circulating levels of angiotensin-(1-7) have been negatively correlated with human persistent constrictive vasculopathies (Takahashi et al., 2010), myocardial infarction (Hao et al., 2013a) and ventricular dysfunction and remodeling (Hao et al., 2013b) due to the relaxant effects triggered by the heptapeptide in human vascular beds (Ueda et al., 2000, Sasaki et al., 2001, van Twist et al., 2013).