Peroxisome Proliferator-Activated Receptor Gamma Promotes Mesenchymal Stem Cells to Express Connexin43 via the Inhibition of TGF-β1/Smads Signaling in a Rat Model of Myocardial Infarction
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In this study, we hypothesized that activation of PPAR-γ enhanced MSCs survival and their therapeutic efficacy via upregulating the expression of Cx43.
MI was induced in 50 male Sprague–Dawley rats. The rats were randomized into five groups: MI group and four intervention groups, including the MSCs group, combined therapy group (MSCs+ pioglitazone), pioglitazone group and PBS group. Two weeks later, 5 × 106 MSCs labeled with PKH26 in PBS were injected into the infarct anterior ventricular free wall in the MSCs and combined therapy groups, and PBS alone was injected into the infarct anterior ventricular free wall in the PBS group. Pioglitazone (3 mg/kg/day) was given to the combined therapy and pioglitazone groups by oral gavage at the same time for another 2 weeks. Myocardial function and relevant signaling molecules involved were all examined thereafter.
Heart function was enhanced after MSCs treatment for 2 weeks post MI. A significant improvement of heart function was observed in the combined therapy group in contrast to the other three intervention groups. Compared with the MSCs group, there was a higher level of PPAR-γ in the combined therapy group; Cx43 was remarkably increased in different regions of the left ventricle; TGF-β1 was decreased in the infarct zone and border zone. To the downstream signaling molecules, mothers against Smad proteins including Smad2 and Smad3 presented a synchronized alteration with TGF-β1; no differences of the expressions of ERK1/2 and p38 could be discovered in the left ventricular cardiac tissue.
MSCs transplantation combined with pioglitazone administration improved cardiac function more effectively after MI. Activation of PPAR-γ could promote MSCs to express Cx43. Inhibition of TGF-β1/Smads signaling pathway might be involved in the process.
KeywordsMesenchymal stem cells Peroxisome proliferator-activated receptor gamma Connexin43 Transforming growth factor beta-1 Decapentaplegic homolog proteins
Mesenchymal Stem Cells
Peroxisome Proliferator-activated Receptor Gamma Cx43 Connexin 43
Transforming growth factor beta-1
Decapentaplegic homolog proteins
Extracellular signal-regulated kinase
This study was supported by Grant 163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology; Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes; National Natural Science Foundation of China (No: 81070125, 81270213), Science and Technology Foundation in Guangdong Province (No: 2010B031600032, 2014A020211002) and the Fundamental Research Funds for the Central Universities (13ykzd16).
Conflict of Interest
The authors declare no conflicts of interest.
This work was done by the investigators of the Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The authors took responsibility for all aspects of the reliability and had no differences in data presentation and interpretation. Jingying Hou and Linyun Wang carried out the experiments and drafted the manuscript; Yue Xing, Tianzhu Guo, Shaoxin Zheng and Changqing Zhou participated in the preparation of the animal model, tissue staining, and molecular assay; Jinghui Hou, Hui Huang and Jingfeng Wang provided the technical assistance; Huibao Long, Tingting Zhong and Quanhua Wu participated the statistical analysis; Tong Wang conceived the study and participated in the study design. All the authors have read and approved the final manuscript.
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