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
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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DOI：
10.1007/s12015-015-9615-7
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发表时间：
2015-12-01
影响因子：
4.8
通讯作者：
Wang, Tong
中科院分区：
文献类型：
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作者：
Hou, Jingying;Wang, Lingyun;Wang, Tong
背景在本研究中，我们假设PPAR-γ的激活通过上调Cx43的表达来提高MSCs的存活率和治疗效果。将大鼠随机分为5组：MI组和4个干预组，包括MSCs组、联合治疗组(MSCs+吡格列酮)、吡格列酮组和PBS组。2周后，MSCs组和联合治疗组将5×10(6)PBS标记的MSCs注入梗死前室游离壁，PBS组仅将PBS注入梗死前室游离壁。联合治疗组和吡格列酮组同时给予吡格列酮3 mg/(kg·d)灌胃，连续2周。结果心肌梗死后骨髓间充质干细胞治疗2周后心功能明显改善。与其他三个干预组相比，联合治疗组的心功能有显著改善。与MSCs组相比，联合治疗组PPAR-γ水平升高，Cx43在左心室不同部位明显升高，梗死区和交界区转化生长因子-β1降低。在下游信号分子方面，Smad2、Smad3等Smad2和Smad3蛋白的表达与转化生长因子β1同步改变，ERK1/2和p38在左心室心肌组织中的表达无明显差异。结论骨髓间充质干细胞移植联合吡格列酮治疗能更有效地改善心肌梗死后的心功能。激活PPAR-γ可促进MSCs表达Cx43。抑制转化生长因子-β1/Smads信号通路可能参与了这一过程。
Background In this study, we hypothesized that activation of PPAR-gamma 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 x 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-gamma in the combined therapy group; Cx43 was remarkably increased in different regions of the left ventricle; TGF-beta 1 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-beta 1; 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-gamma could promote MSCs to express Cx43. Inhibition of TGF-beta 1/Smads signaling pathway might be involved in the process.