Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Mol Cell Endocrinol. 2012 Apr 4;351(2):208-19. doi: 10.1016/j.mce.2011.12.010. Epub 2011 Dec 19.
Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.
血管紧张素转换酶 2（ACE-2）是一种膜相关的羧肽酶，可催化血管收缩素（ANG）-II 转化为血管扩张肽 ANG 1-7。鉴于肾素血管紧张素系统的扩展轴，我们研究了奥美沙坦（10mg/kg/天）在实验性自身免疫性心肌炎中的心脏保护作用。与载体处理的大鼠相比，奥美沙坦治疗可有效抑制心肌中炎症标志物的蛋白表达。然而，与载体处理的大鼠相比，奥美沙坦治疗组的 ACE-2 和 ANG 1-7 及其受体 Mas 的蛋白和 mRNA 水平上调。与载体处理的大鼠相比，奥美沙坦治疗组磷酸化 p38 丝裂原活化蛋白激酶（MAPK）、磷酸化 JNK、磷酸化 ERK 和磷酸化（MAPK）激活蛋白激酶-2 的表达水平显著降低。此外，与正常大鼠相比，载体处理的大鼠的 NADPH 氧化酶亚基（p47phox、p67phox 和 Nox-4）、心肌凋亡标志物和内质网应激标志物的蛋白表达上调，而这些作用都有望通过奥美沙坦下调。此外，奥美沙坦治疗可预防载体处理的 EAM 大鼠中磷酸肌醇-3-激酶（PI3K）和磷酸化 Akt 的蛋白水平降低。我们的结果表明，奥美沙坦治疗的有益作用在对抗炎症、氧化应激、细胞凋亡和与心力衰竭相关的信号通路方面更有效，至少部分是通过调节 ANG 1-7 mas 受体。
