Lu Hung-I, Tong Meng-Shen, Chen Kuan-Hung, Lee Fan-Yen, Chiang John Y, Chung Sheng-Ying, Sung Pei-Hsun, Yip Hon-Kan
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
Am J Transl Res. 2018 Aug 15;10(8):2290-2305. eCollection 2018.
This study tested the hypothesis that entresto therapy effectively protected heart and lung against cardiopulmonary syndrome (CPS) caused by transverse aortic constriction (TAC) in rat. Adult-Male SD rats (n = 36) were equally categorized into group 1 [sham-operated control (SC)], group 2 [SC + enalapril (7 mg/kg/day) since day-28 after TAC induction], group 3 [SC + entresto (30 mg/kg/day) since day-14 after TAC induction], group 4 (TAC only), group 5 (TAC + enalapril) and group 6 (TAC + entresto) and euthanized at day 60 after TAC induction. By day 60, the left-ventricular (LV) ejection fraction was significantly lower in group 4 than in other groups and significantly lower in groups 5 and 6 than in groups 1 to 3, whereas the ratios of heart and lung weights to tibial-length as well as the right-ventricular-systolic blood pressure exhibited an opposite pattern among the groups (all P<0.001). The sarcomere-length (SL), LV fibrotic area, cardiomyocyte size, and lung injury score were highest in group 4, lowest in groups 1 to 3 and significantly lower in group 6 than in group 5 (all P<0.0001). The protein expressions of fibrotic (Smad3/TGF-β), apoptotic (mitochondrial-Bax/cleaved-caspase3/PARP) and DNA-damaged (γ-H2AX) markers in lung and LV myocardium as well as oxidative (NOX-1/NOX2/oxidized protein) in LV myocardium exhibited an identical pattern of SL (all P<0.0001). The protein expressions of pressure/volume overload (BNP/MHC-β) mitochondrial-damaged (cytosolic cytochrome-C) of LV myocardium exhibited an identical pattern of SL (all P<0.001). In conclusion, Entresto is non-inferior to enalapril for protecting the heart-lung against CPS.
恩格列净疗法能有效保护心脏和肺免受大鼠主动脉缩窄（TAC）所致的心肺综合征（CPS）影响。成年雄性SD大鼠（n = 36）被平均分为1组[假手术对照组（SC）]、2组[自TAC诱导后第28天起为SC + 依那普利（7 mg/kg/天）]、3组[自TAC诱导后第14天起为SC + 恩格列净（30 mg/kg/天）]、4组（仅TAC）、5组（TAC + 依那普利）和6组（TAC + 恩格列净），并在TAC诱导后第60天实施安乐死。到第60天时，4组的左心室（LV）射血分数显著低于其他组，5组和6组显著低于1至3组，而心脏和肺重量与胫骨长度的比值以及右心室收缩压在各组间呈现相反模式（均P<0.001）。4组的肌节长度（SL）、LV纤维化面积、心肌细胞大小和肺损伤评分最高，1至3组最低，6组显著低于5组（均P<0.0001）。肺和LV心肌中纤维化（Smad3/TGF-β）、凋亡（线粒体Bax/裂解的半胱天冬酶3/PARP）和DNA损伤（γ-H2AX）标志物的蛋白表达以及LV心肌中的氧化（NOX-1/NOX2/氧化蛋白）与SL呈现相同模式（均P<0.0001）。LV心肌中压力/容量过载（BNP/MHC-β）、线粒体损伤（胞质细胞色素C）的蛋白表达与SL呈现相同模式（均P<0.001）。总之，在保护心肺免受CPS影响方面，恩格列净不劣于依那普利。
