Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA.
Br J Pharmacol. 2018 Jan;175(2):246-261. doi: 10.1111/bph.13983. Epub 2017 Oct 2.
Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation.
H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen peroxide (H O ) or with glucose oxidase (GOx, which generates H O in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR.
Olaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H O , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2.
Olaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation.
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
奥拉帕利、鲁卡帕利和尼拉帕利是聚（ADP-核糖）聚合酶（PARP）的强效抑制剂，已在人类中被批准为抗癌药物。鉴于 PARP 先前在各种形式的急性和慢性心肌损伤中的作用，我们测试了奥拉帕利在心肌细胞氧化应激的体外模型以及心脏移植的体内模型中的作用。
用 vehicle 或奥拉帕利（10μM）预处理的 H9c2-胚胎大鼠心脏衍生的成肌细胞分别用过氧化氢（H2O2）或葡萄糖氧化酶（GOx，其在组织培养基中产生 H2O2）进行挑战。进行细胞活力测定（MTT、乳酸脱氢酶）和 PARP 及其产物 PAR 的 Western 印迹分析。在 Lewis 大鼠中进行异位心脏移植；受体分别用 vehicle 或奥拉帕利（10mg/kg）处理。通过 Millar 导管监测移植心脏的左心室功能。通过 qPCR 测量移植物中的多个基因表达。
奥拉帕利阻断了 PARP1 的自身 PAR 化，并减轻了 H2O2诱导的 H9c2 细胞的快速死亡，但不影响 GOx 诱导的慢性、长期氧化应激后的细胞死亡。在大鼠中，移植后，奥拉帕利改善了左心室收缩和舒张功能。在移植心脏中，奥拉帕利还降低了 c-jun、caspase-12、过氧化氢酶和 NADPH 氧化酶-2 的基因表达。
奥拉帕利保护心肌细胞免受氧化应激，并改善了心脏移植大鼠的移植物收缩性。这些发现提出了重新利用这种临床批准的肿瘤药物的可能性，将其用于心脏移植。
本文是主题为“发明新药而不重新发明轮子：药物再利用的力量”的专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc。
