Wang Jiangyou, Chen Han, Zhou You, Su Qiang, Liu Tao, Li Lang
Cell Physiol Biochem. 2017;41(1):67-78. doi: 10.1159/000455950. Epub 2017 Jan 23.
BACKGROUND/AIMS: In addition to its cardiotonic effect, levosimendan has been thought to have multiple cardiovascular benefits, including anti-inflammatory and anti-apoptotic. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been revealed to be up-regulated in circumstances of coronary microembolization (CME), and the PTEN signaling pathway mediates myocardial apoptosis in swine after CME. However, whether this functional protein could be modified by pretreatment of levosimendan in models of CME has not been disclosed yet.
Swine CME was induced by intra-coronary injection of inertia plastic microspheres (diameter 42µm) into left anterior descending coronary, with or without pretreatment of levosimendan or PTEN siRNA. Echocardiologic measurements, Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining and western blotting were applied to assess their functional, morphological and molecular effects in CME.
PTEN mRNA and protein were aberrantly up-regulated in cardiomyocytes following CME. Furthermore, down-regulation of PTEN in vivo via siRNA was associated with an improved cardiac function, attenuated myocardial apoptosis, and concomitantly inhibited expressions of key proapoptotic proteins such as caspase-3. Interestingly, levosimendan could markedly attenuate PTEN expression and inhibit myocardial apoptosis, therefore partially reverse cardiac dysfunction.
Modulation of PTEN was probably as a potential mechanism involved in the beneficial effects of pretreatment of levosimendan to cardiac function and apoptosis in animal models of CME.
背景/目的：除了具有强心作用外，左西孟旦还被认为具有多种心血管益处，包括抗炎和抗凋亡作用。已发现在冠状动脉微栓塞（CME）情况下，第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）会上调，并且PTEN信号通路介导CME后猪的心肌细胞凋亡。然而，在CME模型中，左西孟旦预处理是否能修饰这种功能性蛋白尚未见报道。
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，同时给予或不给予左西孟旦或PTEN小干扰RNA（siRNA）预处理。应用超声心动图测量、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色和蛋白质印迹法评估它们在CME中的功能、形态和分子效应。
CME后心肌细胞中PTEN mRNA和蛋白异常上调。此外，通过siRNA在体内下调PTEN与心脏功能改善、心肌细胞凋亡减轻相关，并同时抑制了关键促凋亡蛋白如半胱天冬酶-3的表达。有趣的是，左西孟旦可显著减弱PTEN表达并抑制心肌细胞凋亡，从而部分逆转心脏功能障碍。
PTEN的调节可能是左西孟旦预处理对CME动物模型心脏功能和细胞凋亡产生有益作用的潜在机制。
