HIPK2在病理性心肌肥厚中的作用及其机制研究

HIPK2 is a member of homologous domain interaction protein kinase family which is highly expressed in the heart. HIPK2 has been previously reported to be downregulated in exercise-induced physiological cardiac hypertrophy. The upstream regulator of HIPK2 called microRNA-222 is a key molecule involved in exercise-induced physiological cardiac hypertrophy, which prevents cardiac remodeling and heart failure. However, the role of HIPK2 in pathological cardiac hypertrophy and heart failure remains unclear. In our preliminary study, we observed that HIPK2 was markedly upregulated in the mouse model of pathological cardiac hypertrophy, while knockout of HIPK2 attenuated pathological cardiac hypertrophy. Also, we identified ADAMTS4 as a potential downstream target of HIPK2. The present project will first use cell and animal models of pathological cardiac hypertrophy to clarify the role of HIPK2 in pathological cardiac hypertrophy. Then, we will perform functional rescue assays to investigate whether HIPK2 mediates pathological cardiac hypertrophy through upregulating ADAMTS4. Finally, cellular and molecular biology experiments will be conducted to clarify whether HIPK2 activates ADAMTS4 transcription through phosphorylation of p65. Our project suggest that inhibiting HIPK2 might protect against pathological cardiac hypertrophy and HIPK2 can serve as a novel therapeutic target for heart failure.

HIPK2是同源结构域相互作用蛋白激酶家族的成员，在心脏组织高表达。先前报道HIPK2在运动诱导生理性心肌肥厚时下调；其上游微小RNA-222是介导运动诱导生理性心肌肥厚的关键分子，可以保护心室重构和心力衰竭。然而，HIPK2在病理性心肌肥厚和心力衰竭中的作用尚不清楚。通过预实验，我们发现HIPK2在病理性心肌肥厚的小鼠模型中显著上调，而敲除HIPK2可以改善病理性心肌肥厚，并筛选出ADAMTS4是HIPK2潜在的下游分子。本项目将首先在细胞和动物水平的病理性心肌肥厚模型中，明确HIPK2和病理性心肌肥厚的关系。其次，通过功能逆转实验，阐明HIPK2上调ADAMTS4介导病理性心肌肥厚的分子机制。最后，通过细胞分子生物学实验，揭示HIPK2通过磷酸化p65激活ADAMTS4转录的分子基础。本项目将有望明确抑制HIPK2保护病理性心肌肥厚中的作用，为心力衰竭提供新的治疗靶点。

心力衰竭是威胁人类健康的心血管疾病，病理性心室重构是慢性心力衰竭发生发展的主要病理基础。目前心室重构缺乏有效的防治方法，因此探索心室病理性重构的潜在靶点具有非常重要的临床意义。本项目明确HIPK2在小鼠TAC诱导的病理性心机肥厚模型和PE诱导的心机细胞病理性肥大模型中均表达升高。其次在动物水平（HIPK2基因敲除的小鼠及TAC手术的小鼠）和细胞水平（苯肾上腺素PE诱导的大鼠心肌细胞肥大模型）明确抑制HIPK2保护心肌细胞病理性肥大，从而保护小鼠病理性心室重构。在机制方面，我们明确HIPK2通过调控EGR3和CLEC4D，进而调控心肌细胞病理性肥大和小鼠病理性心室重构。本项目提出抑制HIPK2可以防治心肌细胞病理性肥大从而防治心室病理性重构，为心室病理性重构的治疗提供新靶点。