Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury.
Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury.
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DOI：
10.1161/atvbaha.112.245134
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Taylor JM
中科院分区：
文献类型：
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作者：
Cheng Z;DiMichele LA;Hakim ZS;Rojas M;Mack CP;Taylor JM
我们先前报道了心肌局部粘附激酶（FAK）的缺失加剧了缺血/再灌注（I/R）后的心肌细胞死亡。在这里，我们询问是否有针对性地提高心肌FAK活性可以保护心脏免受I/R损伤。产生肌细胞特异性表达FAK变体（称为SuperFAK）的转基因小鼠，其赋予升高的变构激活。在无应激的转基因心脏中FAK活性适度升高，但这对合成代谢心脏生长或心脏功能没有明显影响。重要的是，SuperFAK心脏在I/R后24-72小时表现出FAK活性的显著增加和心肌细胞凋亡和梗死面积的减少。此外，连续超声心动图显示，转基因小鼠在手术后长达8周的时间内免受心脏失代偿的影响。机制研究表明，FAK活性升高通过增强再灌注早期（30和60分钟）NF-κ B依赖的存活信号保护心肌细胞免受I/R诱导的凋亡。此外，在培养的心肌细胞中，腺病毒介导的SuperFAK表达减弱了H2 O2或缺氧/复氧诱导的细胞凋亡，而使用药理学抑制剂或小干扰RNA阻断NF-κB通路完全消除了SuperFAK的有益作用。增强心脏FAK活性可通过激活促存活NF-κB通路减弱I/R诱导的心肌细胞凋亡，这可能代表缺血性心脏病的一种新的治疗策略。
We previously reported that cardiac-restricted deletion of focal adhesion kinase (FAK) exacerbated myocyte death following ischemia/reperfusion (I/R). Here we interrogated whether targeted elevation of myocardial FAK activity could protect the heart from I/R injury. Transgenic mice were generated with myocyte-specific expression of a FAK variant (termed SuperFAK) that conferred elevated allosteric activation. FAK activity in unstressed transgenic hearts was modestly elevated, but this had no discernable effect on anabolic heart growth or cardiac function. Importantly, SuperFAK hearts exhibited a dramatic increase in FAK activity and a reduction in myocyte apoptosis and infarct size 24–72 hrs following I/R. Moreover, serial echocardiography revealed that the transgenic mice were protected from cardiac de-compensation for up to 8 weeks following surgery. Mechanistic studies revealed that elevated FAK activity protected cardiomyocytes from I/R-induced apoptosis by enhancing NF-κB-dependent survival signaling during the early period of reperfusion (30 and 60 minutes). Moreover, adenoviral-mediated expression of SuperFAK in cultured cardiomyocytes attenuated H2O2 or hypoxia/re-oxygenation-induced apoptosis, whereas blockade of the NF-κB pathway using a pharmacological inhibitor or small interfering RNAs completely abolished the beneficial effect of SuperFAK. Enhancing cardiac FAK activity attenuates I/R-induced myocyte apoptosis through activation of the pro-survival NF-κB pathway and may represent a novel therapeutic strategy for ischemic heart diseases.