Sukumaran Vijayakumar, Tsuchimochi Hirotsugu, Tatsumi Eisuke, Shirai Mikiyasu, Pearson James T
Department of Artificial Organs, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan; Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
Biochem Pharmacol. 2017 Nov 15;144:90-99. doi: 10.1016/j.bcp.2017.07.022. Epub 2017 Aug 5.
Hyperglycemia up-regulates intracellular angiotensin II (ANG-II) production in cardiac myocytes. This study investigated the hemodynamic and metabolic effects of azilsartan (AZL) treatment in a mouse model of diabetic cardiomyopathy and whether the cardioprotective effects of AZL are mediated by the angiotensin converting enzyme (ACE)-2/ANG 1-7/Mas receptor (R) cascade. Control db/+ and db/db mice (n=5 per group) were treated with vehicle or AZL (1 or 3mg/kg/d oral gavage) from the age of 8 to 16weeks. Echocardiography was then performed and myocardial protein levels of ACE-2, Mas R, ATR, ATR, osteopontin, connective tissue growth factor (CTGF), atrial natriuretic peptide (ANP) and nitrotyrosine were measured by Western blotting. Oxidative DNA damage and inflammatory markers were assessed by immunofluorescence of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). Compared with db/+ mice, the vehicle-treated db/db mice developed obesity, hyperglycemia, hyperinsulinemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. AZL treatment lowered blood pressure, fasting blood glucose and reduced peak plasma glucose during an oral glucose tolerance test. AZL-3 treatment resulted in a significant decrease in the expression of cytokines, oxidative DNA damage and cardiac dysfunction. Moreover, AZL-3 treatment significantly abrogated the downregulation of ACE-2 and Mas R protein levels in db/db mice. Furthermore, AZL treatment significantly reduced cardiac fibrosis, hypertrophy and their marker molecules (osteopontin, CTGF, TGF-β1 and ANP). Short-term treatment with AZL-3 reversed abnormal cardiac structural remodeling and partially improved glucose metabolism in db/db mice by modulating the ACE-2/ANG 1-7/Mas R pathway.
高血糖会上调心肌细胞内血管紧张素II（ANG-II）的生成。本研究调查了阿齐沙坦（AZL）治疗对糖尿病性心肌病小鼠模型的血流动力学和代谢影响，以及AZL的心脏保护作用是否由血管紧张素转换酶（ACE）-2/ANG 1-7/ Mas受体（R）级联介导。将对照db/+和db/db小鼠（每组n = 5）从8周龄至16周龄用赋形剂或AZL（1或3mg/kg/d口服灌胃）进行治疗。然后进行超声心动图检查，并通过蛋白质印迹法测量ACE-2、Mas R、ATR、ATR、骨桥蛋白、结缔组织生长因子（CTGF）、心钠素（ANP）和硝基酪氨酸的心肌蛋白水平。通过8-羟基-2'-脱氧鸟苷（8-OHdG）、肿瘤坏死因子（TNF）-α和白细胞介素6（IL-6）的免疫荧光评估氧化DNA损伤和炎症标志物。与db/+小鼠相比，用赋形剂治疗的db/db小鼠出现肥胖、高血糖、高胰岛素血症和舒张功能障碍，以及心脏肥大和纤维化。AZL治疗可降低血压、空腹血糖，并在口服葡萄糖耐量试验期间降低血浆葡萄糖峰值。AZL-3治疗导致细胞因子表达、氧化DNA损伤和心脏功能障碍显著降低。此外，AZL-3治疗显著消除了db/db小鼠中ACE-2和Mas R蛋白水平的下调。此外，AZL治疗显著降低了心脏纤维化、肥大及其标志物分子（骨桥蛋白、CTGF、TGF-β1和ANP）。用AZL-3进行短期治疗可通过调节ACE-2/ANG 1-7/Mas R途径逆转db/db小鼠异常的心脏结构重塑并部分改善葡萄糖代谢。
