心力衰竭是心血管疾病终末期结局之一，缺乏治愈方法，探索防治靶点具有重要意义。我们前期发现HIPK3在心力衰竭小鼠的心脏组织中显著上调，细胞水平上，HIPK3在心肌细胞肥大和凋亡过程中表达量升高，其下调可以抑制心肌细胞肥大和凋亡。既往研究表明组织蛋白酶K（CatK）通过调节心肌细胞凋亡和心肌纤维化促进病理性心肌肥厚（PCH）的发生，而HIPK3可以促进CatK启动子区域的转录因子c-Jun的磷酸化，提示：HIPK3是调控PCH和心力衰竭的重要分子，可以通过调节CatK，促进心肌细胞凋亡与心肌纤维化。为验证该假说，以HIPK3基因敲除和AAV9介导心肌特异性敲除或过表达HIPK3小鼠为基础，本申请项目拟采用现代生物学手段探究：1）HIPK3与PCH和心力衰竭的关系；2）HIPK3介导PCH和心力衰竭的分子机制。本研究将明确HIPK3在PCH和心力衰竭中的作用，为心力衰竭的防治提供新靶点。

Heart failure is one of the most common end-stage outcomes of cardiovascular diseases, and lacks of an effective care. Finding new therapies to target heart failure are urgently needed. Our previous studies have found that expression of homeodomain-interacting protein kinase 3 (HIPK3) was elevated in heart from mice with heart failure. In vivo, we found HIPK3 was increased in hypertrophic myocardial cells and apoptotic cardiomyocytes, and all these changes were improved after HIPK3 downregulation. Mechanistically, the article respectively reported the role of cathepsin K (CatK) in promoting pathological cardiac hypertrophy (PCH) by regulating cardiomyocytes apoptosis and myocardial fibrosis, and HIPK3 can contribute to the phosphorylation of c-Jun as a transcription factor in the promoter region of CatK. These data suggested that HIPK3 is an important molecule in the regulation of PCH and heart failure, and can promote cardiomyocytes apoptosis and myocardial fibrosis by regulating CatK. To test this hypothesis, using systemic and AAV9 mediated myocardial specific HIPK3 knockout or overexpression mice as model, this study aims to examine: 1) The relationship of HIPK3 with PCH and heart failure; 2) The molecular mechanism of HIPK3 involved in PCH and heart failure. This study will clarify the role of HIPK3 in PCH and heart failure and provide a new target for the prevention and treatment of heart failure.