Wang Jiangyou, Chen Han, Su Qiang, Zhou You, Liu Tao, Li Lang
Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Cardiac Surgery, Wuhan Asia Heart Hospital in China, Wuhan, China.
J Cardiovasc Pharmacol Ther. 2016 Sep;21(5):471-7. doi: 10.1177/1074248415624158. Epub 2016 Feb 4.
BACKGROUND/AIMS: Phosphatase and the tensin homolog deleted on chromosome ten (PTEN) has been recognized as a promoter of apoptosis in various tissues and has been shown to be upregulated in circumstances of coronary microembolization (CME). We hypothesized that the upregulation of PTEN correlates with CME-induced myocardial apoptosis.
Swine CME was induced by an intracoronary injection of inert plastic microspheres (diameter of 42 μm) into the left anterior descending coronary, with or without pretreatment of the PTEN small-interfering RNA (siRNA). Echocardiological measurements, a pathological examination, Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining, and Western blotting, were performed to assess their functional, morphological, and molecular effects in CME.
PTEN was aberrantly upregulated in cardiomyocytes following CME. Downregulation of PTEN in vivo via siRNA was associated with improved cardiac function and attenuated myocardial apoptosis; concomitantly inhibited the expression of key proapoptotic proteins, such as phosphorylated Bad (p-Bad); cleaved caspase-3; and enhanced the expression of key antiapoptotic proteins, such as phosphorylated protein kinase B (p-Akt). However, there was no difference in the Akt-regulated downstream protein IκB kinases (IKKα, IKKβ, and IKKγ) among the sham, CME, and control siRNA groups.
This study demonstrates, for the first time, that the PTEN/Akt signaling pathway contributes to cardiomyocyte apoptosis. The data generated from this study provide a rationale for the development of PTEN-based therapeutic strategies for CME-induced myocardial injury.
背景/目的：第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）已被公认为多种组织中细胞凋亡的促进因子，并且在冠状动脉微栓塞（CME）情况下显示其表达上调。我们推测PTEN的上调与CME诱导的心肌细胞凋亡相关。
通过向冠状动脉左前降支内注射惰性塑料微球（直径42μm）诱导猪发生CME，部分猪在注射前进行PTEN小干扰RNA（siRNA）预处理。进行超声心动图测量、病理检查、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色和蛋白质免疫印迹分析，以评估其对CME的功能、形态和分子效应。
CME后心肌细胞中PTEN异常上调。通过siRNA在体内下调PTEN与改善心脏功能和减轻心肌细胞凋亡相关；同时抑制关键促凋亡蛋白的表达，如磷酸化的Bad（p-Bad）；裂解的半胱天冬酶-3；并增强关键抗凋亡蛋白的表达，如磷酸化的蛋白激酶B（p-Akt）。然而，在假手术组、CME组和对照siRNA组之间，Akt调节的下游蛋白IκB激酶（IKKα、IKKβ和IKKγ）没有差异。
本研究首次证明PTEN/Akt信号通路促成心肌细胞凋亡。本研究产生的数据为开发基于PTEN的CME诱导心肌损伤治疗策略提供了理论依据。
