Pillai Jyothish B, Gupta Madhu, Rajamohan Senthilkumar B, Lang Roberto, Raman Jai, Gupta Mahesh P
Dept. of Surgery, MC 5040, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1545-53. doi: 10.1152/ajpheart.01124.2005. Epub 2006 Apr 21.
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 microM) treatment significantly increased protein synthesis in PARP(+/+) myocytes, as measured by (3)H-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 microM), 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 Sir2alpha 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.
聚（ADP - 核糖）聚合酶 -1（PARP）是一种与染色质结合的酶，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成部分，因此推测 PARP 可能是血管紧张素 II 诱导的导致心脏肥大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 注入野生型（PARP(+/+)）和 PARP 缺陷型小鼠体内。血管紧张素 II 注入显著增加了 PARP(+/+)小鼠的心脏重量与胫骨长度比值、心肌细胞横截面积和间质纤维化，但在 PARP(-/-)小鼠中未出现这种情况。为了证实这些结果，我们分析了血管紧张素 II 对原代心肌细胞培养物的影响。与 PARP(-/-)心肌细胞相比，血管紧张素 II（1 microM）处理显著增加了 PARP(+/+)心肌细胞中的蛋白质合成，这通过将（3）H - 亮氨酸掺入总细胞蛋白来测量。血管紧张素 II 介导的心肌细胞肥大伴随着核蛋白多聚 ADP - 核糖基化增加和细胞内 NAD 含量的消耗。当用诱导细胞死亡剂量的血管紧张素 II（10 - 20 microM）处理细胞时，在 PARP(+/+)心肌细胞中观察到强烈的心肌细胞死亡，但在 PARP(-/-)心肌细胞中未观察到。这种类型的细胞死亡可通过补充细胞内 NAD 水平以及激活长寿因子 Sir2alpha 脱乙酰酶来阻断，这表明 PARP 的诱导以及随后的 NAD 水平消耗是导致血管紧张素 II 介导的心肌细胞死亡的一系列事件。总之，这些结果表明 PARP 是血管紧张素 II 介导的导致心脏肥大的细胞信号传导的核整合因子，并表明这可能是心力衰竭治疗的一个新的治疗靶点。
