心衰是心血管系统疾病终末期和心源性死亡主要原因之一。研究表明心衰心室肌缝隙连接蛋白43（CX43）重构与心功能降低、心律失常和心肌细胞凋亡的发生密切相关，但确切机制尚未明了。在前一项国自然基金项目中发现：1）在正常心室肌CX43丝氨酸279/282磷酸化是细胞间通讯上调的关键位点，该双位点突变致细胞间通讯显性失活和心肌细胞凋亡；2）心衰动物心室肌CX43重构伴随丝氨酸279/282磷酸化显著减少。因此，本项目首次提出CX43丝氨酸279/282磷酸化是调控心室肌细胞间通讯和心肌存活的重要位点，并可能是心衰心肌CX43重构、细胞间通讯退减和细胞凋亡的重要途径之一。本课题拟验证丝氨酸279/282磷酸化位点的生理作用，和其磷酸化改变致心肌细胞凋亡的机制及在CX43重构，心功下调和心肌凋亡中的作用，从而，可能揭示心衰CX43重构的分子（氨基酸）机制，为心衰预防和治疗提供新的理论依据。

Heart failure (HF) is the end stage of many cardiovascular diseases and one of the leading causes of heart death. It has been demonstrated that connexin 43 (CX43), the dominant connexin in ventricle, is redistributed laterally from the ends of the ventricular myocytes, dephosphorylated and functional down-regulated in failure hearts. These changes due to heart failure are called CX43 remodeling and are implicated to the genesis of arrhythmias, dysfunction and apoptosis in failure heart. However, the mechanisms underlying how CX43 remodeling and involved in the pathological alterations are not clear. We have found in our previous study supported by National Nature Science Foundation that 1) in neonatal rat ventricular myocytes, serine 279/282 (S279/282) phosphorylations in CX43 C terminal upregulate the intercellular communication. Mutations at S279 and S282 cause dominant negative-effect of gap junction and even cell death; 2) in animal failure hearts, CX43 remodeling and dephosphorylations at S279/282 are found. Thus, we hypothesize that S279/282 is the key regulator of ventricular intercellular communication and cell survival. Changes in their phosphorylation status may be involved in the genesis of CX43 remodeling, downregulation of gap junction function and cell apoptosis. In this study, we investigate the role of S279/282 phosphorylations physiologically, and in the genesis and progress of heart failure, in particular, focusing on the CX43 remodeling/heart remodeling and cardiomyocyte apoptosis using molecular biological, physiological and pharmacological approaches. We hope this study may provide the molecular mechanisms underlying how CX43 remodeling occurs and CX43-induced cell apoptosis in heart failure, which may be helpful to seek potential target for the treatment and prevention of heart failure.