Department of Emergency Intensive Care Unit, Zhejiang Provincial People's Hospital, Hangzhou 310014, China.
Acta Pharmacol Sin. 2013 Nov;34(11):1386-96. doi: 10.1038/aps.2013.91. Epub 2013 Sep 30.
To investigate the mechanisms underlying the protective effects of sodium tanshinone IIA sulfonate (STS) in an ischemia-reperfusion (I/R)-induced rat myocardial injury model.
Male SD rats were iv injected with STS, STS+LY294002 or saline (NS) for 15 d. Then the hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Cardiac function, infarction size and area at risk were assessed. Cell apoptosis was evaluated with TUNEL staining, DNA laddering and measuring caspase-3 activity. In addition, isolated cardiomyocytes of neonatal rats were pretreated with the above drugs, then exposed to H2O2 (200 mol/L) for 1 h. Cell apoptosis was detected using flow cytometric assay. The levels of p-Akt, p-FOXO3A and Bim were examined with immunoblotting.
Compared to NS group, administration of STS (20 mg/kg) significantly reduced myocardial infarct size (40.28%±5.36% in STS group vs 59.52%±7.28% in NS group), and improved the myocardial function as demonstrated by the increased values of dp/dtmax, LVDP and coronary flow at different reperfusion time stages. Furthermore, STS significantly decreased the rate of apoptotic cells (15.11%±3.71% in STS group vs 38.21%±7.83% in NS group), and reduced caspase-3 activity to nearly a quarter of that in NS group. Moreover, STS significantly increased the phosphorylation of Akt and its downstream target FOXO3A, and decreased the expression of pro-apoptotic gene Bim. Co-treatment with the PI3K inhibitor LY294002 (40 mg/kg) partially countered the protective effects induced by STS treatment. In isolated cardiomyocytes, STS exerted similar protective effects as shown in the ex vivo I/R model.
STS pretreatment reduces infarct size and improves cardiac function in an I/R-induced rat myocardial injury model via activation of Akt/FOXO3A/Bim-mediated signal pathway.
探讨丹参酮ⅡA 磺酸钠（STS）在缺血再灌注（I/R）诱导的大鼠心肌损伤模型中的保护作用机制。
雄性 SD 大鼠静脉注射 STS、STS+LY294002 或生理盐水（NS）15d。然后，心脏进行 30min 缺血，再灌注 2h。评估心功能、梗死面积和危险区面积。采用 TUNEL 染色、DNA 梯状带和测定 caspase-3 活性评估细胞凋亡。此外，用上述药物预处理新生大鼠分离的心肌细胞，然后用 H2O2（200μmol/L）孵育 1h。采用流式细胞术检测细胞凋亡。用免疫印迹法检测 p-Akt、p-FOXO3A 和 Bim 的水平。
与 NS 组相比，STS（20mg/kg）给药显著降低心肌梗死面积（STS 组为 40.28%±5.36%，NS 组为 59.52%±7.28%），并改善心肌功能，表现为不同再灌注时间阶段 dp/dtmax、LVDP 和冠脉流量的增加值增加。此外，STS 显著降低凋亡细胞的比率（STS 组为 15.11%±3.71%，NS 组为 38.21%±7.83%），并将 caspase-3 活性降低至 NS 组的近四分之一。此外，STS 显著增加 Akt 及其下游靶标 FOXO3A 的磷酸化，并降低促凋亡基因 Bim 的表达。用 PI3K 抑制剂 LY294002（40mg/kg）共同处理部分抵消了 STS 处理诱导的保护作用。在分离的心肌细胞中，STS 表现出与体外 I/R 模型相似的保护作用。
STS 预处理通过激活 Akt/FOXO3A/Bim 介导的信号通路，减少 I/R 诱导的大鼠心肌损伤模型中的梗死面积并改善心功能。
