Fu F-Y, Chen B-Y, Chen L-L, Zhang F-L, Luo Y-K, Jun F
Department of Cardiology, Union Hospital, Fujian Medical University, Fuzhou, P. R. China.
Eur Rev Med Pharmacol Sci. 2016 Jun;20(11):2368-81.
As the impairment of myocardial micro-environments with local inflammatory reactions due to coronary micro-embolization (CME) reduces the survival of transplanted stem cells (SCs). We hypothesized that rosuvastatin treatment could improve the SC survival and enhance their therapeutic effects.
Rat bone marrow-derived mesenchymal stem cells (BMSCs) were infected with lentivirus carrying the green fluorescent protein (GFP) gene. To develop a CME model, rats were injected with a suspension of microthrombotic particles (MTPs) into the left ventricle to obstruct the ascending aorta. GFP-BMSCs were injected with MTPs simultaneously. Rosuvastatin treatment was started 7 days before BMSC transplantation and ended 7 days after transplantation.
Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were examined by the molecular methods. GFP-positive BMSCs were detected by fluorescence staining. Neovascularization was determined by immunohistochemistry. Myocardial morphology was identified by H&E and Masson's trichrome staining. Cardiac function was quantified by echocardiography. Three days after CME, the multifocal myocardial necrosis with extensive infiltration of inflammatory cells was observed, accompanied by high expression of TNF-α and IL-1β. Rosuvastatin treatment reduced the infiltration of inflammatory cells and TNF-α and IL-1β expression. 28 days after transplantation, BMSC therapy with rosuvastatin promoted the survival of implanted cells by ≈45-fold while compared with BMSC therapy alone. BMSC therapy with rosuvastatin (instead of BMSC therapy alone) upregulated the VEGF and bFGF expression, increased the capillary density and improved the cardiac function.
These data suggested that rosuvastatin treatment promoted the survival of transplanted SCs and enhanced their therapeutic effects for CME.
由于冠状动脉微栓塞（CME）导致的心肌微环境损伤及局部炎症反应会降低移植干细胞（SCs）的存活率。我们推测瑞舒伐他汀治疗可提高SCs的存活率并增强其治疗效果。
用携带绿色荧光蛋白（GFP）基因的慢病毒感染大鼠骨髓间充质干细胞（BMSCs）。为建立CME模型，将大鼠左心室内注射微血栓颗粒（MTPs）混悬液以阻塞升主动脉。同时将绿色荧光蛋白标记的骨髓间充质干细胞与微血栓颗粒一起注射。在骨髓间充质干细胞移植前7天开始瑞舒伐他汀治疗，并在移植后7天结束。
采用分子方法检测肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的表达。通过荧光染色检测绿色荧光蛋白阳性的骨髓间充质干细胞。通过免疫组织化学测定新生血管形成。用苏木精-伊红染色和马松三色染色鉴定心肌形态。通过超声心动图对心功能进行定量分析。冠状动脉微栓塞后3天，观察到多灶性心肌坏死，伴有炎症细胞广泛浸润，同时肿瘤坏死因子-α和白细胞介素-1β高表达。瑞舒伐他汀治疗减少了炎症细胞浸润以及肿瘤坏死因子-α和白细胞介素-1β的表达。移植后28天，与单独的骨髓间充质干细胞治疗相比，瑞舒伐他汀联合骨髓间充质干细胞治疗使植入细胞的存活率提高了约45倍。瑞舒伐他汀联合骨髓间充质干细胞治疗（而非单独的骨髓间充质干细胞治疗）上调了血管内皮生长因子和碱性成纤维细胞生长因子的表达，增加了毛细血管密度并改善了心功能。
这些数据表明，瑞舒伐他汀治疗可促进移植干细胞的存活并增强其对冠状动脉微栓塞的治疗效果。
