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首页> 外文期刊>American Journal of Physiology >Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts.
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Poly(ADP-ribose) polymerase-1 hyperactivation and impairment of mitochondrial respiratory chain complex I function in reperfused mouse hearts.

机译：聚（ADP-核糖）聚合酶-1过度激活和线粒体呼吸链复合体I在再灌注小鼠心脏中的功能受损。

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摘要

Poly(ADP-ribose) polymerase-1 (PARP-1), the most abundant member of the PARP family, is a nuclear enzyme that catalyzes ADP-ribose transfer from NAD+ to specific acceptor proteins in response to DNA damage. Excessive PARP-1 activation is an important cause of infarction and contractile dysfunction in heart tissue during interruptions of blood flow. The mechanisms by which PARP-1 inhibition and disruption dramatically improve metabolic recovery and reduce oxidative stress during cardiac reperfusion have not been fully explored. We developed a mouse heart experimental protocol to test the hypothesis that mitochondrial respiratory complex I is a downstream mediator of beneficial effects of PARP-1 inhibition or disruption. Pharmacological inhibition of PARP-1 activity produced no deterioration of hemodynamic function in C57BL/6 mouse hearts. Hearts from PARP-1 knockout mice also exhibited normal baseline contractility. Prolonged ischemia-reperfusion produced a selective defect in complex I function distal to the NADH dehydrogenase component. PARP-1 inhibition and PARP-1 gene disruption conferred equivalent protection against mitochondrial complex I injury and were strongly associated with improvement in myocardial energetics, contractility, and tissue viability. Interestingly, ischemic preconditioning abolished cardioprotection stimulated by PARP-1 gene disruption. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine or xanthine oxidase inhibitor allopurinol restored the function of preconditioned PARP-1 knockout hearts. This investigation establishes a strong association between PARP-1 hyperactivity and mitochondrial complex I dysfunction in cardiac myocytes. Our findings advance understanding of metabolic regulation in myocardium and identify potential therapeutic targets for prevention and treatment of ischemic heart disease.
机译：聚（ADP-核糖）聚合酶-1（PARP-1）是PARP家族中最丰富的成员，是一种核酶，可响应DNA损伤而催化ADP-核糖从NAD +转移至特定受体蛋白。 PARP-1过度活化是在血流中断期间心脏组织中梗塞和收缩功能障碍的重要原因。尚未充分探索PARP-1抑制和破坏能显着改善心脏再灌注过程中代谢恢复和降低氧化应激的机制。我们开发了小鼠心脏实验方案，以测试以下假设：线粒体呼吸复合体I是PARP-1抑制或破坏的有益作用的下游介质。在C57BL / 6小鼠心脏中，PARP-1活性的药理抑制作用不会使血液动力学功能降低。 PARP-1基因敲除小鼠的心脏也表现出正常的基线收缩力。长时间的缺血-再灌注在NADH脱氢酶成分的远端产生复合物I功能的选择性缺陷。 PARP-1抑制和PARP-1基因破坏赋予线粒体复合体I损伤同等的保护，并与心肌能量，收缩力和组织活力的改善密切相关。有趣的是，缺血预处理取消了PARP-1基因破坏刺激的心脏保护作用。用抗氧化剂N-（2-巯基丙酰基）-甘氨酸或黄嘌呤氧化酶抑制剂别嘌醇治疗可恢复预处理的PARP-1敲除心脏的功能。这项研究建立了心肌细胞中PARP-1过度活跃与线粒体复合体I功能障碍之间的紧密联系。我们的发现提高了对心肌代谢调节的了解，并确定了预防和治疗缺血性心脏病的潜在治疗靶标。

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