Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion
Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion
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DOI：
10.1152/ajpheart.00270.2003
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发表时间：
2003-10-01
影响因子：
4.8
通讯作者：
Chao, J
中科院分区：
文献类型：
--
作者：
Kato, K;Yin, H;Chao, J
肾上腺髓质素（AM）已被证明可以防止心脏重塑。在这项研究中，我们研究了潜在的作用AM在心肌缺血再灌注（I/R）损伤，通过腺病毒介导的基因传递。AM基因转染一周后，大鼠进行30分钟的冠状动脉闭塞，随后2小时的再灌注。与对照组相比，AM基因转移显著降低了梗死面积与缺血危险面积的比值和持续性心室颤动的发生。AM基因的传递也减弱了细胞凋亡，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和DNA梯状。AM基因转移对心肌梗死范围、心律失常和细胞凋亡的影响可被AM拮抗剂降钙素基因相关肽[CGRP（8-37）]所消除。人AM的表达显著增加了心脏cGMP水平，降低了超氧化物产生、超氧化物密度、NAD（P）H氧化酶活性、p38 MAPK活化和Bax水平。此外，AM增加Akt和Bad磷酸化和Bcl-2水平，但降低caspase-3活化。这些结果表明，AM通过抑制氧化应激诱导的Bax和p38 MAPK磷酸化和激活Akt-Bad-Bcl- 2信号通路来保护I/R损伤中的心肌梗死、心律失常和细胞凋亡。这项技术的成功应用可能对冠状动脉疾病有保护作用。
Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8-37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl- 2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.