高盐摄入可独立于血压升高引起心肌肥厚，心肌细胞Ca2+稳态失衡与能量代谢异常在其中起关键作用。申请者前期研究发现，高盐可上调肾脏SGLT2(Cell Metab,2016)及心脏SGLT1表达，高盐介导心肌肥厚与心肌线粒体功能受损及Sirt3表达下降有关。本研究拟进一步明确高盐致心肌肥厚的机制是否通过上调SGLT1损害心肌线粒体Ca2+稳态，并提出假设：生理状态下SGLT1和钠钙交换子NCX1协同调控心肌细胞离子稳态，但高盐可上调SGLT1并激活反向模式NCX1，导致心肌细胞Ca2+超载，从而抑制AMPK/Sirt3通路损害线粒体功能和能量代谢，促进心肌肥厚的发生。为此我们利用Dahl盐敏感高血压大鼠、SGLT1 flox/floxMyh6-/-心肌条件敲除小鼠和心肌细胞，揭示SGLT1在高盐诱导心肌肥厚中的作用与机制，为临床应用SGLTs抑制剂保护心脏提供新的治疗靶点。

Long-term high-salt diet could induce myocardial hypertrophy independent increasing of blood pressure. Cardiac Ca2+ homeostasis and energy metabolism abnormalities play a key role in its pathogenesis, but the mechanism is not clear. Our previous study found that myocardial hypertrophy caused by high salt is related to impaired oxidative phosphorylation of myocardial mitochondrial respiratory chain enzyme complex I and decreased Sirt3 expression. Inhibition of AMPK/Sirt3 leads to reverse mode NCX1 and mitochondrial Ca2 + overload. Long-term high-salt diet can increase the expression of Cardiac SGLT1 protein, but the mechanism of high-salt regulates AMPK/Sirt3-mediated directional pattern NCX1 pathway through SGLT1, causing mitochondrial calcium homeostasis and mitochondrial energy metabolism disorders deserved further study. Therefore，we propose a theoretical hypothesis: under physiological conditions, SGLT1 and NCX1 coordinately regulate the ion homeostasis of cardiomyocytes, but long-term high salt intake can upregulate SGLT1, increase intracellular Na+, and activate reverse mode NCX1, resulting in cardiomyocyte Ca2+ overload. Thus inhibiting AMPK/Sirt3 activity impairs mitochondrial function and promotes the occurrence of myocardial hypertrophy. This study will reveal the mechanism of high salt upregulates SGLT1 and damages myocardial mitochondrial Ca2 + homeostasis, resulting in myocardial hypertrophy.