Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Israel; Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Israel.
Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Exp Cell Res. 2018 Dec 15;373(1-2):112-118. doi: 10.1016/j.yexcr.2018.10.003. Epub 2018 Oct 23.
Type 2 diabetes mellitus (DM2) follows impaired glucose tolerance in obesity and is frequently associated with hypertension, causing adverse myocardial remodelling and leading to heart failure. The DNA bound protein PARP (poly ADP ribose) polymerase catalyses a post translational modification (polymerization of negatively charged ADP-ribose chains) of nuclear proteins. PARP-1 activation is NAD dependent and takes part in DNA repair and in chromatin remodelling and has a function in transcriptional regulation, intracellular trafficking and energy metabolism. PARP-1 is activated in diabetic cardiomyopathy. We hypothesized that PARP-1 inhibition in diabetic mice may protect cardiomyocytes from inflammation and ROS production.
Obese Leptin resistant (db/db) mice suffering from DM2, were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly treated with the PARP-1 inhibitor INO1001. Neonatal cardiomyocytes exposed to high levels of glucose (33 mM) with or without AT were treated with INO1001. or with SIRT inhibitor (EX-527) in the presence of INO1001 were tested in-vitro.
The in-vivo tests show that hearts from AT treated DM2 mice exhibited cardiac hypertrophy, fibrosis and an increase in the inflammatory marker TNFα. DM2 mice had an increased oxidative stress, concomitant with elevated PARP-1 activity and reduced Sirtuin-1 (SIRT1) expression. PARP-1 inhibition led to increased SIRT1 and Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) levels, attenuating oxidative stress, inflammation and fibrosis. In-vitro experiments demonstrated that inhibition of PARP-1 in cardiomyocytes exposed to high levels of glucose and AT led to a significant reduction in ROS (P < 0.01), which was abolished in the presence of the SIRT1 inhibitor together with increased protein expression of SIRT1 and PGC-1α.
PARP1 inhibitor INO1001 attenuated cardiomyopathic features in diabetic mice through the activation of SIRT1 and its downstream antioxidant defence mechanisms. The results of this study suggest a pivotal role of PARP-1 inhibition in treating diabetic and AT-induced cardiomyopathy.
2 型糖尿病（DM2）在肥胖后出现葡萄糖耐量受损，常伴有高血压，导致心肌重构不良，导致心力衰竭。DNA 结合蛋白 PARP（多聚 ADP 核糖）聚合酶催化核蛋白的翻译后修饰（带负电荷的 ADP-核糖链的聚合）。PARP-1 的激活依赖于 NAD，并参与 DNA 修复、染色质重塑，具有转录调控、细胞内运输和能量代谢的功能。PARP-1 在糖尿病性心肌病中被激活。我们假设在糖尿病小鼠中抑制 PARP-1 可能会保护心肌细胞免受炎症和 ROS 产生的影响。
患有 2 型糖尿病的肥胖瘦素抵抗（db/db）小鼠接受血管紧张素 II（AT）治疗 4 周，以增强心肌病的发展。同时用 PARP-1 抑制剂 INO1001 治疗。将高浓度葡萄糖（33mM）处理的新生心肌细胞与 AT 一起用 INO1001 处理，或在存在 INO1001 的情况下用 SIRT 抑制剂（EX-527）处理，在体外进行测试。
体内试验表明，AT 治疗的 DM2 小鼠心脏表现出心肌肥大、纤维化和炎症标志物 TNFα 增加。DM2 小鼠的氧化应激增加，同时 PARP-1 活性升高，Sirtuin-1（SIRT1）表达降低。PARP-1 抑制导致 SIRT1 和过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1α）水平升高，减轻氧化应激、炎症和纤维化。体外实验表明，在高浓度葡萄糖和 AT 处理的心肌细胞中抑制 PARP-1 会导致 ROS 显著减少（P<0.01），而在存在 SIRT1 抑制剂的情况下，这种减少被消除，同时 SIRT1 和 PGC-1α 的蛋白表达增加。
PARP1 抑制剂 INO1001 通过激活 SIRT1 及其下游抗氧化防御机制，减轻糖尿病小鼠的心肌病特征。这项研究的结果表明，PARP-1 抑制在治疗糖尿病和 AT 诱导的心肌病中具有关键作用。
