Kv4.3钾通道参与病理性心肌肥厚的新机制:Kv4.3-CaMKII-心肌肥厚

Pathological cardiac hypertrophy can deteriorated into heart failure progressively. Heart hypertrophy/heart failure is accompanied with down-regulation of Kv4.3 K+ channel and the mechanism of down-regulation of Kv4.3 K+ in heart hypertrophy/heart failure remains unclear. In our recent work, we find that inhibition or down-regulation of Kv4.3 K+ channel induces cell apoptosis and necrosis through CaMKII activation. CaMKII plays an important role in pathological cardiac hypertrophy and its malignant progression. Therefore, this subject hypothesized that down-regulation of Kv4.3 K+ channel promote the development of pathological cardial hypertrophy through CaMKII activation. In this study, we will detect the new mechanism that Kv4.3-CaMKII involved in pathological cardiac hypertrophy from two aspects of cardiac myocyte hypertrophy and apoptosis in vitro and in vivo by the technology of immunofluorescence, Western blot, real-time PCR. We will carry out this program using pressure overload hypertrophic mice and transgenic mice respectivly. We put forward a new point-of-view that Kv4.3 K+ channel is involved in heart hypertrophy independently of its electric function for the first time.This new view will provide a new strategy for prevention and treatment of heart hypertrophy/heart failure.

病理性心肌肥厚可进行性发展为心力衰竭。心肌肥厚和心衰表现为Kv4.3钾通道表达和功能下降，但Kv4.3钾通道下降在心肌肥厚和心衰中的作用机制仍不明确。本课题前期结果显示抑制或下调Kv4.3钾通道可激活CaMKII，诱导细胞凋亡和坏死。CaMKII在心肌肥厚及其恶性进展过程中具有重要作用，因此本课题提出假设：Kv4.3钾通道下降通过激活CaMKII诱发病理性心肌肥厚的发生发展。本研究拟采用心肌肥厚病理模型从离体细胞水平、在体动物模型和转基因动物水平，应用免疫荧光、Western Blot、实时定量PCR等技术从心肌细胞肥厚和凋亡两方面研究Kv4.3-CaMKII参与病理性心肌肥厚的机制。本项目首次从全新的视角，即非电生理角度阐明Kv4.3钾通道参与病理性心肌肥厚的新机制，为防治心肌肥厚及心衰提供新策略。

本项目围绕Kv4.3钾通道在病理性心肌肥厚时下调的现象探讨其发生机制，揭示了病理性心肌肥厚时骨形成蛋白4通过激活氧化应激产物促进Kv4.3钾通道下调的新机制，为病理性心肌肥厚的防治提供新思路。同时研究证明Kv4.3钾通道促进乳腺癌细胞增殖，发现miRNA-4673通过与KCND3（Kv4.3钾通道编码基因)3’UTR互补结合抑制其表达，进而抑制乳腺癌细胞增殖促进其凋亡，为乳腺癌治疗提供新策略。本课题相关研究结果共发表SCI论文2篇，另有1篇文章已投稿。项目负责人参与获得黑龙江省人民政府科学技术奖励1项、黑龙江省高校科技奖励1项及哈尔滨市自然科学技术学术成果奖励1项、培养研究生2名，本科生1名。