Targeted deletion of p53 prevents cardiac rapture after myocardial infarction in mice
Targeted deletion of p53 prevents cardiac rapture after myocardial infarction in mice
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DOI：
10.1016/j.cardiores.2006.02.001
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发表时间：
2006-06-01
影响因子：
10.8
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Matsusaka, Hidenori;Ide, Tomomi;Tsutsui, Hiroyuki
目的：细胞凋亡在心肌梗死后心脏重构中可能起重要作用。P53是一种广为人知的促凋亡因子。然而，它在这些情况下的病理生理学意义仍不清楚。方法：通过结扎左冠状动脉建立雄性杂合型(P53(+/-)；n=28)和同胞野生型(P53(+/-)；n=29)小鼠的前壁心肌梗死模型。结果：到第7天，P53(+/-)小鼠的存活率显著高于P53(+/+)小鼠(89%比69%，P<；0.05)。值得注意的是，尽管梗塞面积(60+/-2%比59+/-2%，P=NS)、心率(488+/-15次/分比489+/-17次/分，P=NS)或平均动脉压(80+/-2比78+/-3毫米汞柱，P=NS)相似，p53(+/-)小鼠的左心室(LV)破裂发生率(7%比28%，P<；0.05)显著降低。包括巨噬细胞在内的间质细胞渗入心肌梗死后心脏的程度并未因p53基因缺失而改变。此外，P53(+/-)和P53(+/+)心肌梗死小鼠之间的胶原沉积以及酶谱基质金属蛋白酶-2和-9活性是相似的。然而，p53(+/-)小鼠的梗死壁明显较厚。P53(+/-)组梗死区TUNEL阳性细胞数显著低于P53(+/+)组(423+/-86vs.1330+/-275/10(5)个细胞，P<；0.01)。结论：P53参与了心肌梗死后心脏破裂的发生，其机制可能与诱导细胞凋亡有关。抑制P53可能是治疗心肌梗塞后患者的一种潜在有用的治疗策略。(C)2006年欧洲心脏病学会。爱思唯尔出版，版权所有。
Objective: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts.Methods: Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n=28) mice and sibling wild-type (P53(+/-); n = 29) mice by ligating the left coronary artery.Results: By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P=NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P=NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P=NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423 +/- 86 vs. 1330 +/- 275/10(5) cells, P < 0.01).Conclusions: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.