A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway
A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway
复制标题
晚期糖基化终产物的可溶性受体通过 JAK2/STAT3 途径抑制缺血/再灌注引起的心肌细胞凋亡
DOI：
10.1007/s10495-015-1130-4
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发表时间：
2015-08-01
期刊：
影响因子：
7.2
通讯作者：
Du, Feng-he
中科院分区：
文献类型：
--
作者：
Jiang, Xue;Guo, Cai-xia;Du, Feng-he
丹参对缺血再灌注（I/R）诱导的心肌细胞凋亡有保护作用。然而，目前尚不清楚sodium在心脏保护中的信号传导机制。本研究以小鼠心肌缺血再灌注（I/R）为体内模型，以新生大鼠心肌细胞缺血缓冲液为体外模型，探讨了SbR抑制细胞凋亡的心脏保护作用及其可能的分子机制。采用超声心动图和伊文斯蓝/2，3，5-氯化三苯四氮唑评价I/R后的心功能和心肌梗死面积。TUNEL染色及caspase-3活性检测细胞凋亡。在存在和不存在JAK 2抑制剂AG 490的情况下，通过蛋白质印迹分析检测凋亡相关蛋白p53、Bax、Bcl-2、JAK 2/p-JAK 2、STAT 3/p-STAT 3、AKT/p-AKT、ERK/p-ERK、STAT 5A/p-STAT 5A和STAT 6/p-STAT 6的表达。sRAGE（100 μ g/d）改善I/R小鼠心功能：左室射血分数和短轴缩短率分别增加42和57%;梗死面积减少52%，TUNEL阳性心肌细胞减少66%，caspase-3活性减少24%，p53蛋白表达和Bax/Bcl-2比值分别增加29%和88%，p-JAK 2、p-STAT 3和p-AKT蛋白表达分别增加92%、280%和31%。sCRP对I/R后p-ERK 1/2、p-STAT 5A和p-STAT 6蛋白表达无影响。sodium（900 nmol/L）可使心肌细胞TUNEL阳性率降低67%，caspase-3活性降低20%，p53蛋白水平和Bax/Bcl-2比值分别降低58%和86%，p-JAK 2和p-STAT 3蛋白表达分别增加26%和156%，p-AKT蛋白水平增加33%。JAK 2抑制剂AG 490可阻断saponin在I/R后的抗凋亡作用。PI 3 K抑制剂LY 294002可阻断心肌细胞凋亡减少对TUNEL阳性心肌细胞的影响，而ERK 1/2抑制剂PD 98059则不能阻断心肌细胞凋亡减少对caspase-3活性的影响。这些结果表明，在体外和体内，sleep通过激活JAK 2/STAT 3信号通路保护心肌细胞免受I/R诱导的凋亡。
sRAGE can protect cardiomyocytes from apoptosis induced by ischemia/reperfusion (I/R). However, the signaling mechanisms in cardioprotection by sRAGE are currently unknown. We investigated the cardioprotective effect and potential molecular mechanisms of sRAGE inhibition on apoptosis in the mouse myocardial I/R as an in vivo model and neonatal rat cardiomyocyte subjected to ischemic buffer as an in vitro model. Cardiac function and myocardial infarct size following by I/R were evaluated with echocardiography and Evans blue/2,3,5-triphenyltetrazolium chloride. Apoptosis was detected by TUNEL staining and caspase-3 activity. Expression of the apoptosis-related proteins p53, Bax, Bcl-2, JAK2/p-JAK2, STAT3/p-STAT3, AKT/p-AKT, ERK/p-ERK, STAT5A/p-STAT5A and STAT6/p-STAT6 were detected by western blot analysis in the presence and absence of the JAK2 inhibitor AG 490. sRAGE (100 A mu g/day) improved the heart function in mice with I/R: the left ventricular ejection fraction and fractional shortening were increased by 42 and 57 %, respectively; the infarct size was decreased by 52 %, the TUNEL-positive myocytes by 66 %, and activity of caspase-3 by 24 %, the protein expression of p53 and ratio of Bax to Bcl-2 by 29 and 88 %, respectively; protein expression of the p-JAK2, p-STAT3 and p-AKT were increased by 92, 280 and 31 %, respectively. sRAGE have no effect on protein expression of p-ERK1/2, p-STAT5A and p-STAT6 following by I/R. sRAGE (900 nmol/L) exhibited anti-apoptotic effects in cardiomyocytes by decreasing TUNEL-positive myocytes by 67 % and caspase-3 activity by 20 %, p53 protein level and the Bax/Bcl-2 ratio by 58 and 86 %, respectively; increasing protein expression of the p-JAK2 and p-STAT3 by 26 and 156 %, respectively, p-AKT protein level by 33 %. The anti-apoptotic effects of sRAGE following I/R were blocked by JAK2 inhibitor AG 490. The effect of sRAGE reduction on TUNEL-positive myocytes and caspase-3 activity were abolished by PI3K inhibitor LY294002, but not ERK 1/2 inhibitor PD98059. These results suggest that sRAGE protects cardiomyocytes from apoptosis induced by I/R in vitro and in vivo by activating the JAK2/STAT3 signaling pathway.