Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy
Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy
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DOI：
10.1152/ajpheart.01124.2005
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发表时间：
2006-10-01
影响因子：
4.8
通讯作者：
Gupta, Mahesh P.
中科院分区：
文献类型：
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作者：
Pillai, Jyothish B.;Gupta, Madhu;Gupta, Mahesh P.
聚（ADP-核糖）聚合酶-1（PARP）是一种染色质结合酶，可被细胞氧化应激激活。由于氧化应激也被认为是血管紧张素II介导的细胞信号传导的主要组分，因此推测PARP可能是导致心脏肥大的血管紧张素II诱导的信号传导的下游靶点。为了确定PARP在血管紧张素II诱导的肥大中的作用，我们将血管紧张素II输注到野生型（PARP（+/+））和PARP缺陷小鼠中。血管紧张素II输注显著增加了PARP（+/+）小鼠的心脏重量与胫骨长度的比值、肌细胞横截面积和间质纤维化，但在PARP（-/-）小鼠中没有。为了证实这些结果，我们分析了血管紧张素II在心肌细胞原代培养中的作用。当与PARP（-/-）心肌细胞相比，血管紧张素II（1 μ M）治疗显着增加PARP（-/-）心肌细胞的蛋白质合成，作为测量的H-3-亮氨酸掺入到总细胞蛋白。血管紧张素II介导的心肌细胞肥大伴随着核蛋白的多聚ADP核糖基化增加和细胞NAD含量的耗竭。当用细胞死亡诱导剂量的血管紧张素II（10-20 μ M）处理细胞时，在PARP（+/+）中观察到强烈的肌细胞死亡，但在PARP（-/-）肌细胞中未观察到。这种类型的细胞死亡被细胞NAD水平的补充以及长寿因子Sir 2 α脱乙酰酶的激活所阻断，表明PARP诱导和随后NAD水平的耗尽是导致血管紧张素II介导的心肌细胞死亡的事件序列。总之，这些结果表明，PARP是血管紧张素II介导的细胞信号传导的核整合剂，有助于心脏肥大，并表明这可能是心力衰竭管理的新治疗靶点。
Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP(+/+)) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP(+/+) but not in PARP(-/-) mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP(-/-) cardiomyocytes, angiotensin II (1 mu M) treatment significantly increased protein synthesis in PARP(-/-) myocytes, as measured by H-3-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10-20 mu M), robust myocyte cell death was observed in PARP(+/+) but not in PARP(-/-) myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2 alpha deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.