Differential effects of Akt1 signaling on short- versus long-term consequences of myocardial infarction and reperfusion injury.
Differential effects of Akt1 signaling on short- versus long-term consequences of myocardial infarction and reperfusion injury.
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DOI：
10.1038/labinvest.2014.95
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发表时间：
2014-10
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Akt 1在心肌梗死（MI）和缺血/再灌注（I/R）损伤后事件中的具体作用尚不清楚。我们的目的是确定是否Akt 1缺失在体内小鼠模型的MI和缺血I/R损伤后，将改变心肌细胞存活，心脏功能和纤维化。对Akt 1 +/+和Akt 1 −/−小鼠进行MI和I/R，然后评估下游信号传导事件和功能后果。虽然在Akt 1 +/+和Akt 1 −/−小鼠之间观察到短期MI后的梗死面积没有差异，但与Akt 1 +/+相比，I/R在Akt 1 −/−小鼠中引起了更多的心肌细胞凋亡和组织损伤。重要的是，这些作用在GSK-3抑制剂SB 415286预处理后逆转。与直觉相反，与Akt 1 +/+相比，Akt 1 −/−心脏在长期MI后表现出心脏功能改善，并与左心室（LV）纤维化减少相关。我们的研究结果表明，Akt 1介导的GSK-3活性抑制对于I/R后的心脏保护至关重要。然而，从长远来看，Akt 1有助于心肌梗死后心脏的纤维化，并可能加剧心功能不全，表明Akt 1在心肌梗死后心脏重塑中的双重作用。我们的数据表明，更好地了解Akt 1/GSK-3通路可能会为MI后组织提供更好的治疗策略。
A specific role for Akt1 in events following myocardial infarction (MI) and ischemia/reperfusion (I/R) injury is not known. We aimed to determine whether Akt1 deletion in in vivo mouse models of MI and after ischemia I/R injury would alter myocyte survival, cardiac function, and fibrosis. Akt1+/+ and Akt1−/− mice were subjected to MI and I/R, followed by assessment of downstream signaling events and functional consequences. Although no difference in infarct size following short-term MI was observed between Akt1+/+ and Akt1−/− mice, I/R caused substantially more cardiomyocyte apoptosis and tissue damage in Akt1−/− mice compared with Akt1+/+. Importantly, these effects were reversed upon pretreatment with GSK-3 inhibitor SB415286. Counterintuitively, Akt1−/− hearts exhibited improved cardiac function following long-term MI compared with Akt1+/+ and were associated with reduced fibrosis in the left ventricle (LV). Our results demonstrate that Akt1-mediated inhibition of GSK-3 activity is critical for cardioprotection following I/R. However, in the long term, Akt1 contributes to fibrosis in post-MI hearts and might exacerbate cardiac dysfunction showing dichotomous role for Akt1 in cardiac remodeling after MI. Our data suggest that better understanding of the Akt1/GSK-3 pathway may provide insights for better therapeutic strategies in post-MI tissues.
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影响因子：
82.9
作者：
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