高盐激活TRPC3/NCX1诱导心肌线粒体钙超载致心肌肥厚的机制

心肌细胞Ca2+调控异常与心肌肥厚关系密切，但机制尚不明确。我们前期研究发现高盐可上调心肌瞬时受体电位通道TRPC3表达，促进TRPC3与钠钙交换子(NCX1)介导的心肌细胞内Ca2+和Na+增加，从而导致心肌线粒体功能异常。有报道盐诱导激酶SIK2与细胞内离子稳态调控有关，并参与调节细胞能量平衡。但高盐调控TRPC3介导SIK2在心肌肥厚中的作用尚不清楚。我们提出假说：“高盐激活TRPC3/NCX1介导细胞内Na+与Ca2+增加，促进SIK2调节组蛋白去乙酰化酶HDAC4，从而增强TRPC3/NCX1介导的线粒体-肌浆网结构偶联MAMs形成，导致心肌细胞线粒体钙超载，促使心肌肥厚发生”。以高盐干预TRPC3-/-及同窝野生型小鼠为模型，原代培养心肌细胞及H9C2心肌细胞系，揭示高盐激活TRPC3-NCX1介导心肌钙调节异常促使心肌肥厚发生的机制, 为高盐导致心脏损害的防治提供理论依据。

Transient receptor potential channel TRPC3 control intracellular Ca2+ and ROS production plays an important role in high salt-induced myocardial hypertrophy. Increased intracellular Na+ activates salt-induced kinase SIK2. We confirmed that high salt can increase myocardial TRPC3 and SIK2 expression, TRPC3 gene knockout can prevent high salt induced myocardial hypertrophy, high salt increase cardiomyocytes Ca2+ and Na+ related to TRPC3 and NCX1. For this reason, we put forward our hypothesis: "Under physiological salt conditions, TRPC3 and NCX1 co-regulate the steady balance of sodium and calcium ions in cardiomyocytes, and maintain the mitochondrial function of cardiomyocytes. In high salt conditions, activation of TRPC3 mediated cardiomyocytes Na+, Ca2+ signal abnormal, increased intracellular Na+ activates reverse mode NCX1 mediated [Ca2+]cyt increased, result activation of SIK2 raised histone deacetylase HDAC5 promotes NCX1-TRPC3 complex formation, leading to mitochondria [ Ca2+]m overload, inhibites the key enzyme activity in mitochondrial respiratory chain and increases ROS production, and promotes myocardial hypertrophy induced by high salt. " It is proposed to use TRPC3 gene knockout mice as animal model，combined with the cultured cardiomyocytes and the cell line of H9C2 rats to reveal the mechanism of high salt activating TRPC3-NCX1 mediated mitochondrial dysfunction caused by abnormal myocardial calcium signal. This study provides a theoretical basis for the prevention and treatment of myocardial hypertrophy induced by high salt.