Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction

Zhong,Ze; Hu,Jia-Qing; Wu,Xin-Dong; Sun,Yong; Jiang,Jun

doi:10.3892/ijmm.2015.2261

Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction

Authors:
- Ze Zhong
- Jia-Qing Hu
- Xin-Dong Wu
- Yong Sun
- Jun Jiang
View Affiliations

Affiliations: The Second Affiliated Hospital (Jiande Branch), Department of Cardiology, Zhejiang University School of Medicine, Jiande, Zhejiang 311600, P.R. China
Published online on: June 25, 2015 https://doi.org/10.3892/ijmm.2015.2261
Pages: 753-759

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Myocardin-related transcription factor-A (MRTF-A) can transduce biomechanical and humoral signals, which can positively modulate cardiac damage induced by acute myocardial infarction (AMI). In the clinic, bone marrow stem cell (BMSC) therapy is being increasingly utilized for AMI; however, the effects of BMSC transplantation remain to be optimized. Therefore, a novel strategy to enhance BMSC‑directed myocardial repair is particularly important. The present study was performed to assess the efficacy of MRTF‑A-overexpressing BMSCs in a rat model of AMI. Primary cardiomyocytes were prepared from neonatal Sprague-Dawley rats and BMSCs were isolated from male Sprague-Dawley rats (aged 8-12 weeks). Annexin V-phycoerythrin/7-actinomycin D staining was used to evaluate BMSC and cardiomyocyte survival after exposure to hydrogen peroxide in vitro. B-cell lymphoma 2 (Bcl-2) protein expression was measured by flow cytometric and western blot analyses. The effects of MRTF-A‑overexpressing BMSCs in a rat model of AMI were investigated by hematoxylin and eosin staining and western blot analysis of Bcl-2 expression in myocardial tissue sections. MRTF-A enhanced the migration of BMSCs, and overexpression of MRTF-A in BMSCs prevented hydrogen peroxide-induced apoptosis in primary cardiomyocytes ex vivo. In addition, co-culture of cardiomyocytes with MRTF‑A-overexpressing BMSCs inhibited hydrogen peroxide-induced apoptosis and the enhanced expression of Bcl-2. Furthermore, in vivo, enhanced cell survival was observed in the MRTF-A-modified BMSC group compared with that in the control group. These observations indicated that MRTF-A-overexpressing BMSCs have the potential to exert cardioprotective effects against hydrogen peroxide-induced injury and that treatment with MRTF‑A‑modified BMSCs is able to reverse cardiac dysfunction after AMI.

View Figures

View References

1	Sabbah HN and Sharov VG: Apoptosis in heart failure. Prog Cardiovasc Dis. 40:549–562. 1998. View Article : Google Scholar : PubMed/NCBI
2	Mill JG, Stefanon I, dos Santos L and Baldo MP: Remodeling in the ischemic heart: the stepwise progression for heart failure. Braz J Med Biol Res. 44:890–898. 2011. View Article : Google Scholar : PubMed/NCBI
3	Takemura G and Fujiwara H: Role of apoptosis in remodeling after myocardial infarction. Pharmacol Ther. 104:1–16. 2004. View Article : Google Scholar : PubMed/NCBI
4	Hausenloy DJ and Yellon DM: Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest. 123:92–100. 2013. View Article : Google Scholar : PubMed/NCBI
5	Jeong H, Yim HW, Cho Y, Park HJ, Jeong S, Kim HB, Hong W and Kim H: The effect of rigorous study design in the research of autologous bone marrow-derived mononuclear cell transfer in patients with acute myocardial infarction. Stem Cell Res Ther. 4:822013. View Article : Google Scholar : PubMed/NCBI
6	Fisher SA, Dorée C, Brunskill SJ, Mathur A and Martin-Rendon E: Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: A systematic review and meta-analysis. PLoS One. 8:e646692013. View Article : Google Scholar : PubMed/NCBI
7	Gnecchi M, He H, Liang OD, et al: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 11:367–368. 2005. View Article : Google Scholar : PubMed/NCBI
8	Behfar A, Zingman LV, Hodgson DM, Rauzier J-M, Kane GC, Terzic A and Pucéat M: Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 16:1558–1566. 2002. View Article : Google Scholar : PubMed/NCBI
9	Williams AR, Suncion VY, McCall F, Guerra D, Mather J, Zambrano JP, Heldman AW and Hare JM: Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. J Am Heart Assoc. 2:e0001402013. View Article : Google Scholar : PubMed/NCBI
10	Forest VF, Tirouvanziam AM, Perigaud C, Fernandes S, Fusellier MS, Desfontis JC, Toquet CS, Heymann MF, Crochet DP and Lemarchand PF: Cell distribution after intracoronary bone marrow stem cell delivery in damaged and undamaged myocardium: Implications for clinical trials. Stem Cell Res Ther. 1:42010. View Article : Google Scholar : PubMed/NCBI
11	Li W, Ma N, Ong LL, et al: Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells. 25:2118–2127. 2007. View Article : Google Scholar : PubMed/NCBI
12	Das H, George JC, Joseph M, et al: Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model. PLoS One. 4:e73252009. View Article : Google Scholar : PubMed/NCBI
13	Pipes GC, Creemers EE and Olson EN: The myocardin family of transcriptional coactivators: Versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 20:1545–1556. 2006. View Article : Google Scholar : PubMed/NCBI
14	Miano JM: Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol. 35:577–593. 2003. View Article : Google Scholar : PubMed/NCBI
15	Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, Krieg PA and Olson EN: Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell. 105:851–862. 2001. View Article : Google Scholar : PubMed/NCBI
16	Mikhailov AT and Torrado M: In search of novel targets for heart disease: Myocardin and myocardin-related transcriptional cofactors. Biochem Res Int. 2012:9737232012. View Article : Google Scholar : PubMed/NCBI
17	Cao XL, Hu XM, Hu JQ and Zheng WX: Myocardin-related transcription factor-A promoting neuronal survival against apoptosis induced by hypoxia/ischemia. Brain Res. 1385:263–274. 2011. View Article : Google Scholar : PubMed/NCBI
18	Latif N, Sarathchandra P, Chester AH and Yacoub MH: Expression of smooth muscle cell markers and co-activators in calcified aortic valves. Eur Heart J. 36:1335–1345. 2015. View Article : Google Scholar
19	Liao XH, Wang N, Liu QX, Qin T, Cao B, Cao DS and Zhang TC: Myocardin-related transcription factor-A induces cardiomyocyte hypertrophy. IUBMB Life. 63:54–61. 2011. View Article : Google Scholar : PubMed/NCBI
20	Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K and Olson EN: Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res. 107:294–304. 2010. View Article : Google Scholar : PubMed/NCBI
21	Parmacek MS: Myocardin-related transcription factor-A: mending a broken heart. Circ Res. 107:168–170. 2010. View Article : Google Scholar : PubMed/NCBI
22	Guo J, Li HZ, Wang LC, Zhang WH, Li GW, Xing WJ, Wang R and Xu CQ: Increased expression of calcium-sensing receptors in atherosclerosis confers hypersensitivity to acute myocardial infarction in rats. Mol Cell Biochem. 366:345–354. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zhao SL, Zhang YJ, Li MH, Zhang XL and Chen SL: Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction. Stem Cell Res Ther. 5:372014. View Article : Google Scholar : PubMed/NCBI
24	Sacherer M, Sedej S, Wakuła P, et al: CONTICA investigators: JTV519 (K201) reduces sarcoplasmic reticulum Ca^²+ leak and improves diastolic function in vitro in murine and human non-failing myocardium. Br J Pharmacol. 167:493–504. 2012. View Article : Google Scholar : PubMed/NCBI
25	Cai BZ, Meng FY, Zhu SL, et al: Arsenic trioxide induces the apoptosis in bone marrow mesenchymal stem cells by intracellular calcium signal and caspase-3 pathways. Toxicol Lett. 193:173–178. 2010. View Article : Google Scholar : PubMed/NCBI
26	Gao YS, Ding H, Xie XT and Zhang CQ: Osteogenic induction protects rat bone marrowederived mesenchymal stem cells against hypoxia-induced apoptosis in vitro. J Surg Res. 184:873–879. 2013. View Article : Google Scholar : PubMed/NCBI
27	Ning J, Li C, Li H and Chang J: Bone marrow mesenchymal stem cells differentiate into urothelial cells and the implications for reconstructing urinary bladder mucosa. Cytotechnology. 63:531–539. 2011. View Article : Google Scholar : PubMed/NCBI
28	Gnecchi M, Danieli P and Cervio E: Mesenchymal stem cell therapy for heart disease. Vascul Pharmacol. 57:48–55. 2012. View Article : Google Scholar : PubMed/NCBI
29	Clifford D, Fisher S, Brunskill S, Doree C, Mathur A, Watt S and Martin-Rendon E: Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2:CD0065362012.PubMed/NCBI