Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.
Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.
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DOI：
10.1161/circresaha.115.303632
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发表时间：
2014-07-18
影响因子：
20.1
通讯作者：
Pu WT
中科院分区：
文献类型：
--
作者：
Lin Z;von Gise A;Zhou P;Gu F;Ma Q;Jiang J;Yau AL;Buck JN;Gouin KA;van Gorp PR;Zhou B;Chen J;Seidman JG;Wang DZ;Pu WT
是细胞相关蛋白（雅普）是Hippo信号通路的末端效应子，在调控胚胎心肌细胞（CM）增殖中起重要作用。我们假设心肌梗死后雅普激活可以保护心脏功能并提高生存率。我们使用心脏特异性的诱导表达系统来激活成年小鼠心脏中的雅普。成年心脏中雅普的激活促进CM增殖，并且不对心脏功能产生不良影响。此外，心肌梗死（MI）后雅普激活可保护心脏功能并减少梗死面积。使用腺相关病毒亚型9（AAV9）作为递送载体，我们在成年小鼠心肌梗死后立即表达人雅普。我们发现AAV9：hYAP显著改善心脏功能和小鼠存活。AAV9：hYAP没有通过减少CM凋亡发挥其有益作用。相反，AAV9：hYAP刺激成体CM增殖。基因表达谱分析表明，AAV9：hYAP刺激细胞周期基因的表达，并促进较不成熟的心脏基因表达签名。心肌梗死后心脏特异性雅普激活可减轻心肌损伤，改善心功能，提高生存率。这些发现表明，治疗性激活雅普或其下游靶点，可能通过AAV介导的基因治疗，可能是一种策略，以改善MI后的结果。
Yes-Associated Protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte (CM) proliferation. We hypothesized that YAP activation after myocardial infarction would preserve cardiac function and improve survival. We used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted CM proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the adult murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing CM apoptosis. Rather, AAV9:hYAP stimulated adult CM proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated expression of cell cycle genes and promoted a less mature cardiac gene expression signature. Cardiac specific YAP activation after MI mitigated myocardial injury, improved cardiac function, and enhanced survival. These findings suggest that therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.