Smad1 protects cardiomyocytes from ischemia-reperfusion injury
Smad1 protects cardiomyocytes from ischemia-reperfusion injury
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DOI：
10.1161/circulationaha.104.490946
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发表时间：
2005-05-31
期刊：
影响因子：
37.8
通讯作者：
Hirota, H
中科院分区：
文献类型：
--
作者：
Masaki, M;Izumi, M;Hirota, H
背景-我们以前报道过骨形态发生蛋白2（BMP 2）通过Smad 1途径诱导Bcl-xL而保护去血清心肌细胞免于凋亡。为了研究Smad 1信号转导是否促进细胞存活在成年心脏，我们进行了转基因小鼠与心脏特异性过表达的Smad 1基因（Smad 1 TG）缺血-再灌注（I/R）injury.Methods and Results -BMP 2或腺病毒介导的转染Smad 1对心肌细胞存活在缺氧-复氧的影响进行了研究，使用大鼠新生心肌细胞。BMP 2和Smad 1均显著促进缺氧-复氧过程中心肌细胞的存活并减少其凋亡。有趣的是，Smad 1在正常小鼠心脏I/R期间被激活。为了研究Smad 1在I/R中的生理和病理作用，我们使用α-肌球蛋白重链基因启动子产生Smad 1 TG。在所有转基因阳性小鼠心脏中均发现Smad 1磷酸化。为了研究Smad 1是否能预防体内心肌细胞的损伤，我们将Smad 1 TG和年龄匹配的野生型小鼠（WT）进行了1小时的左冠状动脉结扎和1小时的再灌注诱导的I/R损伤。TUNEL和DNA ladder分析显示，Smad 1 TG组心肌梗死面积明显小于WT组，心肌细胞凋亡率明显低于WT组。有趣的是，Bcl-xL和β-连环蛋白的表达增加是更显着的，而半胱天冬酶3激活Smad 1 TG心脏比WT。结论-这些研究结果表明，Smad 1信号通路起着心脏保护作用，对I/R损伤。
Background - We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury.Methods and Results - The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the alpha-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene - positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and beta-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT.Conclusions - These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.