Cardiac-Specific EPI64C Blunts Pressure Overload-Induced Cardiac Hypertrophy
Cardiac-Specific EPI64C Blunts Pressure Overload-Induced Cardiac Hypertrophy
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心脏特异性 EPI64C 可以减弱压力过载引起的心脏肥大
DOI：
10.1161/hypertensionaha.115.07042
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发表时间：
2016-05-01
期刊：
影响因子：
8.3
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
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作者：
Zhu, Xuehai;Fang, Jing;Li, Hongliang
在过去的十年中，钙离子反应分子钙调神经磷酸酶已被很好地表征为在病理性心脏肥大中发挥因果作用。然而，在心肌细胞肥大的进展过程中，钙调神经磷酸酶信号的内在负调节仍然是个谜。在此，我们探讨了EPI 64 C，一种在T细胞活化过程中Ras和钙调磷酸酶信号传导的双重抑制剂，在压力超负荷诱导的心脏肥大中的作用。我们产生了心脏特异性Epi 64 c条件性敲除小鼠品系，并表明Epi 64 c的缺失显著加剧了压力超负荷诱导的心脏肥大。相比之下，心肌细胞特异性Epi 64 c转基因小鼠中的EPI 64 C功能获得对心脏肥大产生有效的保护作用。从机制上讲，EPI 64 C的心脏保护作用主要归因于钙调磷酸酶信号传导的中断，但与其Ras抑制能力无关。分子生物学研究表明，EPI 64 C的406 - 446个C-末端氨基酸直接与钙调神经磷酸酶催化结构域的287 - 337个氨基酸结合，这是EPI 64 C介导的抑制作用的原因。我们进一步将我们的研究外推到食蟹猴，并表明基于慢病毒介导的EPI 64 C在猴心脏中过表达的基因治疗可钝化压力超负荷诱导的心脏肥大。因此，我们的研究确定EPI 64 C作为一种新的负调节剂，在心肌肥厚的靶向钙调神经磷酸酶信号，并证明了潜在的基因治疗和药物开发治疗心肌肥厚。
The calcium-responsive molecule, calcineurin, has been well characterized to play a causal role in pathological cardiac hypertrophy over the past decade. However, the intrinsic negative regulation of calcineurin signaling during the progression of cardiomyocyte hypertrophy remains enigmatic. Herein, we explored the role of EPI64C, a dual inhibitor of both Ras and calcineurin signaling during T-cell activation, in pressure overload-induced cardiac hypertrophy. We generated a cardiac-specific Epi64c conditional knockout mouse strain and showed that loss of Epi64c remarkably exacerbates pressure overload-induced cardiac hypertrophy. In contrast, EPI64C gain-of-function in cardiomyocytespecific Epi64c transgenic mice exerts potent protective effects against cardiac hypertrophy. Mechanistically, the cardioprotective effects of EPI64C are largely attributed to the disrupted calcineurin signaling but are independent of its Ras suppressive capability. Molecular studies have indicated that the 406 to 446 C-terminal amino acids in EPI64C directly bind to the 287 to 337 amino acids in the catalytic domain of calcineurin, which is responsible for the EPI64Cmediated suppressive effects. We further extrapolated our studies to cynomolgus monkeys and showed that gene therapy based on lentivirus-mediated EPI64C overexpression in the monkey hearts blunted pressure overload-induced cardiac hypertrophy. Our study thus identified EPI64C as a novel negative regulator in cardiac hypertrophy by targeting calcineurin signaling and demonstrated the potential of gene therapy and drug development for treating cardiac hypertrophy.