CAJ | 학술논문

背景：前期研究发现骨髓间充质干细胞移植能够改善心肌梗死大鼠的心功能，但整体效果并不太理想。目的：拟采用PPAR-γ激动剂吡格列酮联合骨髓间充质干细胞移植治疗以进一步改善心肌梗死大鼠的心功能并探讨相关机制。方法：开胸结扎20只SD大鼠左前降支冠状动脉并随机分为2组：骨髓间充质干细胞组和骨髓间充质干细胞+吡格列酮组。2周后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，联合治疗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。细胞移植后2周进行超声心动图检测，免疫荧光染色、Western blot、qRT-PCR检测左心室心肌组织不同区域PPAR-γ、TGF-β1/SMAD通路相关因子和Cx43的表达情况。结果与结论：两组大鼠基础心功能参数无明显差异性。细胞移植2周后，骨髓间充质干细胞+吡格列酮组左室舒张末径、左室收缩末径明显减小，左室射血分数明显增高；左心室心肌组织不同区域PPAR-γ和Cx43的表达量显著增加；TGF-β1、SMAD2、SMAD3在梗死区和梗死边缘区表达明显下降。以上结果提示 PPAR-γ激动剂吡格列酮干预能够增强骨髓间充质干细胞移植对心功能的改善作用，其机制可能与 PPAR-γ抑制TGF-β1/SMAD通路进而提高Cx43的表达有关。
배경：전기연구발현골수간충질간세포이식능구개선심기경사대서적심공능，단정체효과병불태이상。목적：의채용PPAR-γ격동제필격렬동연합골수간충질간세포이식치료이진일보개선심기경사대서적심공능병탐토상관궤제。방법：개흉결찰20지SD대서좌전강지관상동맥병수궤분위2조：골수간충질간세포조화골수간충질간세포+필격렬동조。2주후재국부경사심기내주사PKH26표기적유PBS현부적골수간충질간세포，연합치료조재주사골수간충질간세포후여이필격렬동3 mg/(kg?d)련속관위2주。세포이식후2주진행초성심동도검측，면역형광염색、Western blot、qRT-PCR검측좌심실심기조직불동구역PPAR-γ、TGF-β1/SMAD통로상관인자화Cx43적표체정황。결과여결론：량조대서기출심공능삼수무명현차이성。세포이식2주후，골수간충질간세포+필격렬동조좌실서장말경、좌실수축말경명현감소，좌실사혈분수명현증고；좌심실심기조직불동구역PPAR-γ화Cx43적표체량현저증가；TGF-β1、SMAD2、SMAD3재경사구화경사변연구표체명현하강。이상결과제시 PPAR-γ격동제필격렬동간예능구증강골수간충질간세포이식대심공능적개선작용，기궤제가능여 PPAR-γ억제TGF-β1/SMAD통로진이제고Cx43적표체유관。
BACKGROUND:Our previous work has demonstrated that bone marrow mesenchymal stem cels (BMSCs) transplantation can improve the heart function of rats with myocardial infarction. However, the overal efficacy is not satisfactory. OBJECTIVE: To adopt pioglitazone as a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist combined with BMSCs transplantation therapy, thereby further improving cardiac function of rats with myocardial infarction as wel as investigating the relevant mechanisms. METHODS:Twenty Sprague-Dawley rats with myocardial infarction were induced by the left anterior descending coronary artery ligation. The animals were randomized into two groups: BMSCs and BMSCs+pioglitazone. Two weeks later, al the animals received the injection of BMSCs labeled with PKH26 in PBS into the local infarct zone, and then pioglitazone (3 mg/kg/d) was given by the oral gavage for 2 weeks in the BMSCs+pioglitazone group after the cel transplantation. After 2 weeks of cel transplantation, cardiac functions were evaluated by echocardiography. The expressions of PPAR-γ, Connexin 43 and molecules in TGF-β1/SMAD signaling pathway were examined in different areas of the left ventricle from each harvested heart using immunofluorescent staining, western blot assay and qRT-PCR. RESULTS AND CONCLUSION:There were no differences in the baseline parameters of cardiac function between the two groups. At 2 weeks after cel transplantation, the left ventricular internal diameter at end-diastole, left ventricular internal diameter at end-systole and left ventricular ejection fraction were significantly improved in the BMSCs+ pioglitazone group; the expressions of PPAR-γ and Connexin 43 were distinctly increased in different zones of the left ventricle; the levels of TGF-β1, SMAD2 and SMAD3 were obviously attenuated in the infarct zone and border zone. The above-mentioned findings suggest that pioglitazone, a PPAR-γ agonist, can enhance BMSCs potential in improvingthe heart function after myocardial infarction, and PPAR-γ may elevate the expression of Connexin 43via the blockade of the TGF-β1/SMAD signaling pathway in the procedure.