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.
BACKGROUND
In this study, we hypothesized that activation of PPAR-γ enhanced MSCs survival and their therapeutic efficacy via upregulating the expression of Cx43.


METHODS
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 × 10(6) 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.


RESULTS
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.


CONCLUSIONS
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.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Jingying
J
Hou
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Lingyun
L
Wang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Jinghui
J
Hou
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Tianzhu
T
Guo
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Yue
Y
Xing
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.|Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China.
Shaoxin
S
Zheng
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Changqing
C
Zhou
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.|Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China.
Hui
H
Huang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Huibao
H
Long
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Tingting
T
Zhong
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.
Quanhua
Q
Wu
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120.|Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China.
Jingfeng
J
Wang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China, 510120. tongwang316@163.com.|Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China. tongwang316@163.com.|Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China. tongwang316@163.com.
Tong
T
Wang
D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D018031:Connexin 43 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000628:therapy*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D018031:Connexin 43; D047495:PPAR gamma; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077205:Pioglitazone
Connexin43; Decapentaplegic homolog proteins; Mesenchymal stem cells; Peroxisome proliferator-activated receptor gamma; Transforming growth factor beta-1