斑点追踪显像评价CaSR/MAPK信号促进肺动脉高压介导心肌损伤的作用研究

右心功能衰竭是影响肺动脉高压不良预后的重要因素。我们前期工作中研究发现肺动脉高压大鼠外周血钙敏感受体（CaSR）水平明显升高，并提示CaSR通过MAPK信号通路参与心肌重构及细胞凋亡过程，但其机制尚不清楚。我们推测肺动脉高压时心肌细胞CaSR表达增加，激活MAPK/ERK通路诱导心肌细胞凋亡及炎症因子释放，引起右室心肌结构和功能损害。在此基础上通过建立肺动脉高压模型，应用斑点追踪显像（STE）联合免疫学、TUNEL等技术在体内外实验及临床人群研究拟开展：1）STE评估肺动脉高压模型CaSR表达上调及其功能激活对右室心肌结构及功能的影响；2）探讨CaSR对肺动脉高压状态下MAPK/ERK信号、MMP2/9表达及抗凋亡因子bcl-2信号调控作用及机制；3）筛选STE评价肺动脉高压预后不良的敏感指标。为进一步探讨肺动脉高压心肌损伤的机制、影像学指标及新的治疗靶点提供理论和实验依据。

Right heart failure dramatically impacts prognosis in pulmonary hypertension (PH). Our previous work found that the level of calcium sensing receptor (CaSR) in peripheral blood of PH rats was significantly increased, suggesting that CaSR participates in myocardial remodeling and apoptosis through MAPK signaling pathway, but its mechanism is not clear. We speculate that the expression of CaSR in cardiomyocytes increases during PH, and the activation of MAPK/ERK pathway induce apoptosis and the release of inflammatory factors, causing damage to the structure and function of the right heart. This study based on the basis of previous work to establish the PH model, using speckle tracking echocardiography (STE) combined with immunology, TUNEL and other techniques in vivo, in vitro and in population for the following researches: 1) Effects of up-regulation of CaSR expression and its functional activation on the structure and function of right ventricular myocardium in PH model assessed by STE. 2) To investigate the effect and mechanism of CaSR regulating MAPK/ERK pathway, MMP2/9 and the anti-apoptotic factor bcl-2 signal in PH. 3) To screen out the sensitive indexes of STE for predicting poor prognosis of PH. To further explore the mechanism of PH myocardial injury, imaging indicators and new therapeutic targets to provide theoretical and experimental basis.