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背景:过氧化物酶体增殖物激活受体γ激动剂能促进外源性骨髓间充质干细胞的生存和向心肌细胞分化及改善心功能。研究欲进一步验证吡格列酮能否促进内源性骨髓间充质干细胞向心肌细胞的分化及改善心功能的相关机制。目的:比较过氧化物酶体增殖物激活受体γ激动剂吡格列酮联合骨髓间充质干细胞移植治疗、单纯吡格列酮治疗及磷酸缓冲液治疗疗效的差异及其相关机制。方法:开胸结扎30只SD大鼠左前降支冠状动脉并随机分为3组:骨髓间充质干细胞+吡格列酮组、吡格列酮组、磷酸缓冲液组。造模后2周骨髓间充质干细胞+吡格列酮组在局部梗死心肌内注射PKH26标记的由PBS悬浮的骨髓间充质干细胞,吡格列酮组和磷酸缓冲液组在梗死心肌内注射PBS,骨髓间充质干细胞+吡格列酮组和吡格列酮组在注射骨髓间充质干细胞后予以吡格列酮3 mg/(kg·d)连续灌胃2周。治疗2周后检测心功能,摘取心脏检测左心室心肌组织不同区域过氧化物酶体增殖物激活受体γ、缝隙连接蛋白43和TGF-β1/SMAD通路相关因子的表达变化。结果与结论:(1)3组大鼠在干预开始时心功能参数无明显差异性。干预2周后,骨髓间充质干细胞+吡格列酮联合治疗组左室舒张末径、左室收缩末径明显减小,左室射血分数明显增高;(2)骨髓间充质干细胞+吡格列酮组和吡格列酮组左心室心肌组织不同区域过氧化物酶体增殖物激活受体γ表达量显著增加;(3)骨髓间充质干细胞+吡格列酮组在梗死区和梗死边缘区Cx43表达较吡格列酮组和磷酸缓冲液组显著增高,TGF-β1、SMAD2、SMAD3表达明显下降,吡格列酮组与磷酸缓冲液组在上述指标方面表达差异无显著性意义;(4)结果表明,过氧化物酶体增殖物激活受体γ激动剂吡格列酮并不能刺激内源性骨髓间充质干细胞的增殖分化并改进心功能,吡格列酮联合外源性骨髓间充质干细胞能改善心功能,其机制可能与过氧化物酶体增殖物激活受体γ抑制TGF-β1/SMAD通路进而促进外源性骨髓间充质干细胞表达Cx43有关。
BACKGROUND: Peroxisome proliferator-activated receptor gamma agonists promote the survival and differentiation of exogenous bone marrow mesenchymal stem cells and improve cardiac function. To further verify whether pioglitazone can promote the differentiation of endogenous bone marrow mesenchymal stem cells into cardiomyocytes and improve the cardiac function. OBJECTIVE: To compare the efficacy of periadhylene agonist (PPARG) agonist pioglitazone and bone marrow mesenchymal stem cell transplantation in the treatment of pioglitazone and phosphate buffered saline (PBS) and the related mechanisms. Methods Thirty male SD rats were thoracotomized and were randomly divided into 3 groups: BMSCs + pioglitazone group, pioglitazone group and phosphate buffered saline group. The bone marrow mesenchymal stem cells + pioglitazone group at 2 weeks after modeling was injected intraperitoneally with PKH26-labeled MSCs suspended in PBS, pioglitazone group and phosphate buffered saline group, intraperitoneal injection of PBS, bone marrow mesenchymal stem cells Stem cells + pioglitazone group and pioglitazone group were given pioglitazone 3 mg / (kg · d) continuously for 2 weeks after bone marrow mesenchymal stem cells injection. After 2 weeks of treatment, heart function was measured. The cardiac function was measured and the expression of peroxisome proliferator activated receptor γ, connexin 43 and TGF-β1 / SMAD pathway related factors in different regions of left ventricular myocardium were extracted. RESULTS AND CONCLUSION: (1) There was no significant difference in cardiac function parameters between the three groups at the beginning of intervention. After intervention for 2 weeks, left ventricular diastolic dimension, left ventricular end-diastolic diameter and left ventricular ejection fraction were significantly increased in BMSCs plus pioglitazone group. (2) BMSCs + pioglitazone group and The expression of peroxisome proliferator activated receptor γ in pioglitazone group was significantly increased in different regions of myocardium of left ventricle; (3) The expression of Cx43 in bone marrow mesenchymal stem cells + pioglitazone group was higher than that in pioglitazone group and phosphate buffer The expression of TGF-β1, SMAD2 and SMAD3 was significantly decreased in the liquid group, and there was no significant difference in the expression of these indexes between the pioglitazone group and the phosphate buffer group. (4) The results showed that peroxisome proliferator-activated receptor Pioglitazone, a gamma agonist, did not stimulate the proliferation and differentiation of endogenous bone marrow mesenchymal stem cells and improved cardiac function. Pioglitazone combined with exogenous bone marrow mesenchymal stem cells could improve cardiac function, which may be related to the activation of peroxisome proliferator-activated Receptor γ inhibits the TGF-β1 / SMAD pathway and promotes the expression of Cx43 in exogenous bone marrow-derived mesenchymal stem cells.