Pressure overload promotes cystatin C secretion of cardiomyocytes to regulate the MAPK signaling pathway and mediate cardiac hypertrophy.
Pressure overload promotes cystatin C secretion of cardiomyocytes to regulate the MAPK signaling pathway and mediate cardiac hypertrophy.
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压力超负荷促进心肌细胞分泌胱抑素C调节MAPK信号通路介导心肌肥厚
DOI：
10.21037/atm-20-7041
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发表时间：
2020-11
影响因子：
--
通讯作者：
Ge J
中科院分区：
文献类型：
--
作者：
Shen Y;Zhang X;Li C;Wang X;Ye Y;Yuan J;Gong H;Zou Y;Ge J
背景本研究旨在比较高血压与非高血压患者血清胱抑素C （cyysc）水平，探讨血清胱抑素C与左心室肥厚（LVH）的相关性。我们还研究了压力过载对心脏CysC表达和分泌的影响，并探讨了CysC对原代心肌细胞肥大的直接影响。方法比较高血压患者（634例）与非高血压患者（411例）血清CysC水平，探讨血清CysC水平与LVH的相关性。建立了横断主动脉收缩（TAC）小鼠模型和原代心肌细胞和成纤维细胞的机械拉伸模型，比较压力过载下心脏中CysC的表达和分泌。在外源性CysC干预后，我们比较了原代心肌细胞的横截面积、心肌肥大相关基因的表达和MAPK信号通路的磷酸化。结果在慢性肾脏疾病（CKD） 1期患者中，高血压患者血清CysC较高，与肾功能无关。血清CysC升高是内源性肌酐清除率（eCCr）、左心室射血分数（LVEF）和NT-proBNP校正后LVH的独立预测因子。TAC小鼠心脏CysC水平升高。CST3基因表达上调，原代心肌细胞机械拉伸后细胞内和培养上清CysC水平均升高。外源性CysC干预后，原代心肌细胞横截面积增加，Nppa、Nppb、Myh7基因表达增加，ERK、p38、TAK1磷酸化增加。结论高血压患者血清CysC水平较高，血清CysC升高是eCCr校正后LVH的独立预测因子。压力过载诱导心肌细胞分泌更多的CysC。外源性CysC可进入心肌细胞，通过调控MAPK信号通路对原代心肌细胞产生促肥厚作用。
Background This study aimed to compare serum cystatin C (CysC) levels between hypertensive and non-hypertensive patients, and to explore the correlation between serum CysC and left ventricular hypertrophy (LVH). We also investigated the effects of pressure overload on cardiac expression and secretion of CysC, and explored the direct effect of CysC on the hypertrophy of primary cardiomyocytes. Methods Serum CysC was compared in patients with hypertension (634 patients) and those without hypertension (411 patients), and the correlation between serum CysC levels and LVH was explored. A transverse aortic constriction (TAC) mouse model and a mechanical stretch model of primary cardiomyocytes and fibroblasts were developed to compare cardiac expression and secretion of CysC under pressure overload. After intervention with exogenous CysC, we compared the cross-sectional area of primary cardiomyocytes, cardiac hypertrophy-associated gene expression, and phosphorylation of the MAPK signaling pathway. Results In chronic kidney disease (CKD) stage 1 patients, serum CysC was higher in hypertensive patients independent of renal function. Serum CysC elevation was an independent predictor of LVH after correction for endogenous creatinine clearance rate (eCCr), left ventricular ejection fraction (LVEF), and NT-proBNP. Cardiac levels of CysC in TAC mice were elevated. CST3 gene expression was upregulated, and both intracellular and culture supernatant CysC levels increased after mechanical stretch of primary cardiomyocytes. After intervention with exogenous CysC, the cross-sectional area of primary cardiomyocytes increased, as well as the gene expression of Nppa, Nppb, and Myh7, and the phosphorylation of ERK, p38, and TAK1. Conclusions Serum CysC levels were higher in hypertensive patients, and serum CysC elevation was an independent predictor of LVH after correction for eCCr. Pressure overload induced greater cardiomyocyte secretion of CysC. Exogenous CysC can enter cardiomyocytes, having a pro-hypertrophic effect on primary cardiomyocytes through regulation of the MAPK signaling pathways.
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