Sun Yu-Han, Su Qiang, Li Lang, Wang Xian-Tao, Lu Yuan-Xi, Liang Jia-Bao
Department of Cardiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
J Geriatr Cardiol. 2017 May;14(5):292-300. doi: 10.11909/j.issn.1671-5411.2017.05.007.
Cardiomyocyte apoptosis is a primary cause for coronary microembolization (CME)-induced cardiac dysfunction. p53 induces cell growth retardation and apoptosis through stress pathway. The present study investigated the mechanism of p53-induced myocardial apoptosis and cardiac dysfunction by activating the mitochondrion apoptotic pathway following CME.
Forty SD rats were equally divided into microembolization (CME), sham operation (sham), CME+siRNA-p53, and CME+control-p53 groups. The CME rat model was established by injecting microembolization spheres via the left ventricle. Cardiac ultrasound, TUNEL, fluorescence quantitative PCR, and Western blot were used to assess the cardiac function indicators, cardiomyocyte apoptosis, and the expressions of mRNA and protein in myocardial tissues, respectively.
Echocardiography revealed a significantly reduced cardiac function of the CME group than the sham group while the CME-induced cardiac dysfunction was improved in the CME+siRNA-p53 group. The indicators of myocardial apoptosis in the CME group increased significantly than the sham group; those of the CME+siRNA-p53 group decreased significantly than the CME group. Fluorescence quantitative PCR and Western blot demonstrated that p53, Bbc3 (PUMA), and cleaved caspase-3 expressions were significantly increased, and BCL-2 expression was declined in myocardial tissues of the CME group compared to the sham group. A contrasting result was observed in the CME+siRNA-p53 group as compared to the CME group.
P53 is involved in the CME-induced cardiac dysfunction, which may up-regulate Bbc3 to activate BCL-2/caspase3 mitochondrial apoptotic pathway and induce myocardial apoptosis. Inhibiting the p53 expression can effectively suppress this pathway, thereby reducing myocardial apoptosis and cardiac dysfunction.
心肌细胞凋亡是冠状动脉微栓塞（CME）所致心脏功能障碍的主要原因。p53通过应激途径诱导细胞生长迟缓及凋亡。本研究旨在探讨CME后p53通过激活线粒体凋亡途径诱导心肌凋亡及心脏功能障碍的机制。
40只SD大鼠平均分为微栓塞组（CME）、假手术组（sham）、CME+siRNA-p53组和CME+对照-p53组。通过经左心室注射微栓塞球建立CME大鼠模型。分别采用心脏超声、TUNEL、荧光定量PCR及蛋白质印迹法评估心脏功能指标、心肌细胞凋亡以及心肌组织中mRNA和蛋白质的表达。
超声心动图显示，CME组心脏功能明显低于假手术组，而CME+siRNA-p53组CME诱导的心脏功能障碍得到改善。CME组心肌凋亡指标显著高于假手术组；CME+siRNA-p53组显著低于CME组。荧光定量PCR及蛋白质印迹法显示，与假手术组相比，CME组心肌组织中p53、Bbc3（PUMA）及裂解的caspase-3表达显著增加，BCL-2表达下降。与CME组相比，CME+siRNA-p53组结果相反。
P53参与CME诱导的心脏功能障碍，可能通过上调Bbc3激活BCL-2/caspase3线粒体凋亡途径并诱导心肌凋亡。抑制p53表达可有效抑制该途径，从而减少心肌凋亡及心脏功能障碍。
