CUEDC2调节SERCA2α活性参与心力衰竭发生和进展的机制研究

The incidence of heart failure was constantly increasing. However, we have limited approach to treat heart failure. Calcium Imbalance, which was promoted by the decrease of SERCA2a protein and activity, is the main cause of the occurrence and progression of heart failure. However, when we delivered the gene coded CUEDC2 into the heart of patients suffered with heart failure, there was no significant of heart function recovery, indicating that the activity of SERCA2a was much more important. In previous study, we found that the heart function is much better in Cuedc2-/- mouse subjected to Transaortic constriction (TAC), and the activity of SERCA2a was much higher than control mouse. However, we don't the exact mechanism about CUEDC2 modulating SERCA2a activity. Recently, we found that the phosphorylation of CUEDC2 was much higher in patients suffered with heart failure. Therefore, we postulated that the phosphorylation of CUEDC2 promotes the dephosphorylation of PLB, and the activity of SERCA2a subsequently decreased. This might be the main cause of heart failure. Based on this postulation, we plan to construct cardiomyocyte specific CUEDC2 knockout mice and constantly phosphorylated CUEDC2. And to study the mechanism of CUEDC2 on SERCA2a regulation on molecular, cellular and heart level. Importantly, we want to test the effect of CUEDC2 knockdown in heart treatment by interfering the protein level of CUEDC2 in mouse with advanced heart failure. Our study might find a novel target of heart failure.

心衰发病率高，现有治疗手段有限。SERCA2a蛋白水平和活性下降促进心肌细胞“钙失衡”，调控心衰发生和进展。外源性基因表达增强SERCA2a蛋白水平并不能有效改善心功能，提示SERCA2a活性调节更为重要。前期研究发现：缺失CUEDC2蛋白能显著减轻超负荷所致小鼠心功能不全的发生并增强SERCA2a蛋白活性，但确切机制尚不清楚。进一步研究发现CUEDC2蛋白在心衰患者心肌组织中特异性磷酸化。推测：CUEDC2蛋白发生磷酸化，结合PP1，间接增强SERCA2a活性调控蛋白PLB去磷酸化，导致SERCA2a活性下降，调控心衰的发生。研究拟构建心肌细胞特异性CUEDC2敲除小鼠和CUEDC2失活转基因小鼠，在分子、细胞和心脏水平研究CUEDC2在SERCA2a活性调节以及心衰发生中的作用，并以此为基础，研究在体干预CUEDC2对已发心衰的治疗作用。研究期望发现具有原始创新的心衰临床治疗靶标。

心力衰竭（心衰）是各种心血管疾病发展的终末阶段。但是，在终末期心力衰竭的临床治疗上，我们所能应用的治疗手段有限，迫切需要新的治疗策略。在心衰发生过程中，心肌细胞对钙离子处理能力下降导致的心肌细胞内“钙失衡”，是心肌细胞功能障碍的核心环节。研究心肌细胞“钙失衡”的发生机制，并针对“钙失衡”进行有效的临床治疗，一直是心血管领域的研究热点。我们在前期研究中发现了蛋白质CUEDC2在心肌细胞中特异性高表达，敲除CUEDC2后心肌细胞对缺血再灌注损伤所致氧化应激的处理能力明显提高，提示CUEDC2是心肌细胞内一个保守存在的潜在调控蛋白。在本项目中，我们发现：在心力衰竭发生过程中，心肌细胞中的CUEDC2发生特异性的磷酸化，抑制心肌细胞内钙离子关键调控蛋白SERCA2a的活性，进而导致心肌细胞钙失衡。敲除CUEDC2或者是特异性抑制CUEDC2磷酸化以后，心肌细胞钙离子处理能力明显改善，心肌细胞功能恢复。同时，在该项目的资助下，我们继续沿着心肌缺损再灌注损伤后心肌组织修复能力的研究，发现了系统性低氧在心肌缺损损伤中的重要作用，发现了CUEDC2在低氧处理巨噬细胞促进其表型转化中的关键调控作用。研究结果进一步深化了对功能蛋白质CUEDC2的认识，为心肌损伤修复和心力衰竭的机制和临床干预提供了新的治疗策略。在该项目的支持下，申请者团队目前已经发表两篇SCI论著，正在完成撰写和修改的论文有3篇。支持毕业博士研究生两名。