PMC:7161517 / 14762-17804 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7161517","sourcedb":"PMC","sourceid":"7161517","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7161517","text":"Sprague-Dawley rats treated with a 4-week course of Ang II infusion showed Ang II upregulated AT1 receptor, downregulated AT2 receptor, ACE2 activity, endothelial nitric oxide synthase expression, as well as increased CD44 expression and hyaluronidase (45). However, rats treated with telmisartan exhibited significantly increased ACE2 activity and endothelial nitric oxide synthase expression in intracardiac vessels and intermyocardium, as well as downregulated local expression of the AT1 receptor. Treatment with telmisartan also inhibited membrane CD44 expression and reduced transforming growth factor−β and Smad expression (45). Studies in normotensive rats with post-coronary artery ligation left ventricular remodeling and dysfunction exhibited partial resolution following losartan and olmesartan treatment while augmenting plasma concentrations of the angiotensins (46). This was associated with recovery of cardiac AT1 receptor mRNA and increased ACE2 mRNA post-myocardial infarction, which implied the beneficial effects of ARBs on cardiac remodeling were accompanied by direct blockade of AT1 receptors and increased ACE2 expression and/or activity (46). The literature offers conflicting results pertaining to ARB use and the level of ACE2 expression on the myocardium; most of the controversy arises from the difference in ACE2 cell surface expression and plasma ACE2 levels. In the Sprague-Dawley rats with left coronary artery ligation and myocardial infarction, plasma Ang II and Ang1-7 were not elevated, but plasma ACE2 was elevated, along with enhanced cardiac ACE2 and AT1 receptor mRNA at the infarct border (47). Receptor upregulation was not observed in the remote myocardium (47). Treatment with ramipril and valsartan resulted in increased plasma Ang I and Ang II and suppression in plasma ACE and ACE2 activity; however, neither monotherapy nor combination therapy affected ACE2 or AT1 receptor expression, both of which remained at levels comparable to non-myocardial infarction control (47). However, a previous study in the same murine model showed ACE and ACE2 upregulation in the border, infarct zones, and in viable myocardium after myocardial infarction. Treatment with ramipril reduced ACE expression, whereas ACE2 remained elevated compared with the noninfarcted control subject (48). A recent study in the same murine model demonstrated that treatment with olmesartan or telmisartan increased both cardiac ACE2 mRNA and protein expression while augmenting plasma Ang1-7/Ang II ratios, which resulted in improved cardiac function and alleviated collagen disposition (49). These experiments suggested that both ACE inhibitors and ARBs variably upregulated ACE2 expression (49). ARBs inhibited binding of Ang II to the AT1 receptor, which permitted circulating Ang II to be shunted to ACE2 for conversion to Ang1-7. These studies suggest that the ACE2/Ang1-7 axis collaborates with or is regulated by the AT1 receptor and may be important in mediating the vascular and cardiac remodeling effects of Ang 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