程序性细胞死亡分子5（PDCD5）调控心肌肥厚的作用及作用机制

Cardiac hypertrophy is an adaptive response of the heart to diverse pathological stimuli. Compensatory hypertrophy allows the heart to preserve fundamental function and blood circulation; however, sustained hypertrophy is a risk factor of cardiac arrhythmia, heart failure, and sudden death. Thus, the heart must develop an intrinsic defense mechanism to prevent excessive cardiomyocyte hypertrophy. Undoubtedly, the exploration of endogenous hypertrophic suppressors has important implications for the development of therapeutic strategies against cardiac hypertrophy. The programmed cell death 5 (PDCD5) was initially identified as an apoptosis accelerator/enhancer and was later found to be involved in the pathogenesis of various diseases, such as human tumors, autoimmune diseases, inflammatory diseases, influenza, and cerebral ischemia/reperfusion injury. However, the function of PDCD5 in the heart is not yet clear. By generating a cardiac-specific Pdcd5 knockout mouse model (αMHC-Cre+/Pdcd5fl/fl), our preliminary results showed that PDCD5 deficiency in the heart causes severe hypertrophic cardiomyopathy and cardiac dysfunction. In contrast, PDCD5 protein is upregulated in transverse aortic constriction-mediated mouse hypertrophic hearts and PE-stimulated hypertrophic cardiomyocytes. Consistently, knockdown of PDCD5 by adeno-PDCD5 shRNA induces cardiomyocyte hypertrophy while PDCD5 overexpression by adeno-PDCD5 inhibits PE-stimulated cardiomyocyte hypertrophy, indicating that PDCD5 may serve as an endogenous hypertrophic suppressor and provide negative feedback to protect the heart from excessive hypertrophy. In the present study, we will investigate the role of PDCD5 in the pathogenesis of cardiac hypertrophy both in vitro and in vivo, and will reveal the underlying mechanisms.

心肌肥厚是心脏对多种病理性刺激的适应性反应。早期心肌肥厚可代偿性地维持有效心输出量，但持续发展的心肌肥厚最终会导致心衰。因此，心脏必然存在内在保护机制，防止心肌肥厚过度发展。程序性细胞死亡分子5（PDCD5）可促进细胞凋亡，也参与肿瘤等多种疾病的病理过程，但其心脏功能尚不明确。我们预实验发现，PDCD5基因心脏特异性敲除后，小鼠出现显著心脏肥厚；在心肌肥厚小鼠病理模型心脏组织以及肥大心肌细胞中，PDCD5蛋白显著上调。与此一致，心肌细胞中敲低PDCD5导致细胞肥大，而过表达PDCD5则抑制肥大因子诱导的心肌细胞肥大；提示PDCD5可能是心肌肥厚的负反馈抑制因子，在心肌肥厚发展过程中发挥重要作用。本课题拟在心肌细胞水平、心脏特异性PDCD5基因敲除小鼠模型、心肌肥厚小鼠病理模型，深入探讨PDCD5在心肌肥厚发生发展过程中的作用及分子机制，为抑制心肌肥厚过度发展探寻新的干预策略及治疗靶点。

程序性细胞死亡分子5（PDCD5）在人体各组织中广泛存在，尤其在心脏及骨骼肌中高表达，但其心脏功能尚未明确。我们发现肥厚心脏及心肌细胞中PDCD5水平显著升高；心肌特异性敲除Pdcd5基因后，小鼠出现严重心肌肥厚、心功能障碍；在心肌肥厚过程中，经典肥大信号NFAT与Pdcd5基因启动子区结合，激活Pdcd5基因表达；Pdcd5基因敲除后，心肌肌质网钙泵SERCA2a降解增加，细胞钙稳态失衡，细胞舒张功能障碍。此外，我们发现心肌纤维化患者血清中、在心梗后28天心肌纤维化小鼠模型中、以及成纤维细胞中PDCD5水平显著升高；在心脏成纤维细胞中敲低PDCD5可促进细胞分泌纤维化因子，过表达PDCD5则抑制纤维化刺激所致纤维化因子的分泌。心肌纤维化时，Smad3信号直接调控PDCD5基因表达；PDCD5蛋白可与组蛋白去乙酰化酶HDAC3相互作用，促进HDAC3泛素化，从而抑制HDAC3对心肌纤维化的调控；成纤维细胞特异性表达PDCD5转基因小鼠模型，心梗后心肌纤维化及心功能得到改善。我们的研究提示，在心肌肥厚及心肌纤维化过程中，PDCD5作为心脏内源性保护因子，抑制心肌肥厚及纤维化进一步发展恶化。

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