Division of Cardiac Surgery, Heart Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
The Key Laboratory of Assisted Circulation, Ministry of Health, Guangzhou, P.R. China.
J Cardiovasc Pharmacol. 2018 Oct;72(4):176-185. doi: 10.1097/FJC.0000000000000611.
Simvastatin treatment is cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin treatment protects the myocardium under these conditions are not fully understood. Seventy patients undergoing noncoronary cardiac surgery, 35 from a simvastatin treatment group and 35 from a control treatment group, were enrolled in our clinical study. Simvastatin (20 mg/d) was administered preoperatively for 5-7 days. Myocardial tissue biopsies were taken before and after surgery. Apoptosis was detected by TUNEL staining. The expressions of Bcl-2 and Bak in myocardial tissue were detected by immunoblotting. The expressions of miRNA and Bcl-2 mRNA were detected by quantitative real-time polymerase chain reaction assays. Cardiomyocytes were isolated from rat and cultured cells. MiR-15a-5p mimic was transfected into cardiomyocytes, and the Bcl-2 was detected by immunoblotting. TUNEL staining showed significantly less myocardial apoptosis in the simvastatin treatment group when compared with the control treatment group. Protein expression of Bcl-2 was increased in the simvastatin treatment group before surgery, and Bak expression was increased in the control treatment group after surgery. Further comparisons showed that Bcl-2/Bak ratios were reduced in the control treatment group but were not significantly changed in the simvastatin treatment group after surgery. Furthermore, microarray assays revealed that miR-15a-5p was significantly decreased by simvastatin treatment. This was validated by quantitative real-time polymerase chain reaction analysis. MiR-15a-5p was predicted to target Bcl-2 mRNA at nucleotide positions 2529-2536. This was validated by luciferase binding assays. Coincident with the change in miR-15a-5p, the mRNA expression of Bcl-2 was increased in the simvastatin treatment group. MiR-15a-5p mimic significantly inhibited Bcl-2 expression in cardiomyocytes. Our findings strongly suggest that simvastatin treatment preoperatively protected the myocardium in patients undergoing noncoronary artery cardiac surgery, at least in part, by inhibiting apoptosis via suppressing miR-15a-5p expression, leading to increasing expression of Bcl-2 and decreasing expression of Bak.
辛伐他汀治疗可保护行非冠状动脉心脏手术的患者的心肌。然而，辛伐他汀治疗在这些条件下保护心肌的机制尚不完全清楚。我们的临床研究纳入了 70 例行非冠状动脉心脏手术的患者，其中 35 例来自辛伐他汀治疗组，35 例来自对照组。辛伐他汀（20mg/d）术前给药 5-7 天。手术前后取心肌组织活检。TUNEL 染色检测细胞凋亡。免疫印迹法检测心肌组织中 Bcl-2 和 Bak 的表达。实时定量聚合酶链反应检测 miRNA 和 Bcl-2 mRNA 的表达。从小鼠分离心肌细胞并培养。将 miR-15a-5p 模拟物转染至心肌细胞，并用免疫印迹法检测 Bcl-2 的表达。TUNEL 染色显示辛伐他汀治疗组的心肌细胞凋亡明显少于对照组。辛伐他汀治疗组术前 Bcl-2 蛋白表达增加，对照组术后 Bak 表达增加。进一步比较显示，对照组术后 Bcl-2/Bak 比值降低，但辛伐他汀治疗组术后比值无明显变化。此外，微阵列检测显示辛伐他汀治疗可显著降低 miR-15a-5p。实时定量聚合酶链反应分析验证了这一点。miR-15a-5p 被预测在核苷酸位置 2529-2536 处靶向 Bcl-2 mRNA。荧光素酶结合测定验证了这一点。与 miR-15a-5p 的变化一致，辛伐他汀治疗组 Bcl-2 mRNA 的表达增加。miR-15a-5p 模拟物显著抑制心肌细胞中 Bcl-2 的表达。我们的研究结果强烈表明，辛伐他汀术前治疗可通过抑制 miR-15a-5p 表达抑制细胞凋亡，从而增加 Bcl-2 表达和降低 Bak 表达，至少部分保护行非冠状动脉心脏手术的患者的心肌。
