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Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction

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Abstract

Purpose

Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic option for patients with acute myocardial infarction.

Methods

We show here that the ectopic overexpression of endothelial nitric oxide synthases (eNOS), an endothelial form of NOS, could enhance the ability of MSCs in treating ischemic heart damage after the occlusion of the coronary artery.

Results

Adenoviral delivery of human eNOS gene into mouse bone marrow-derived MSCs (BM-MSCs) conferred resistance to oxygen glucose deprivation (OGD)-induced cell death in vitro, and elevated the bioavailability of nitric oxide when injected into the myocardium in vivo. In a rat model of acute myocardial infarction, the transplantation of eNOS-overexpressing BM-MSCs significantly reduced myocardial infarct size, corrected hemodynamic parameters and increased capillary density. We also found that the synergistic effects were consistently better than either treatment alone.

Conclusions

These findings reveal a positive role of elevated eNOS expression in cardiac repair, and suggest the combination of eNOS and MSC transplant therapy as a potential approach for treating myocardial infarction.

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References

  1. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res. 2004;95:9–20.

    Article  CAS  PubMed  Google Scholar 

  2. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med. 2006;12:459–65.

    Article  CAS  PubMed  Google Scholar 

  3. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10:244–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg. 2005;80:229–36. discussion 36-7

    Article  PubMed  Google Scholar 

  5. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105:93–8.

    Article  PubMed  Google Scholar 

  6. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN, et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 2013;10:301–12.

    Article  CAS  PubMed  Google Scholar 

  7. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003;9:1195–201.

    Article  CAS  PubMed  Google Scholar 

  8. Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829–37. 37a-37d

    Article  PubMed  Google Scholar 

  9. Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, et al. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension. 1998;32:521–6.

    Article  CAS  PubMed  Google Scholar 

  10. Colombo MG, Paradossi U, Andreassi MG, Botto N, Manfredi S, Masetti S, et al. Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem. 2003;49:389–95.

    Article  CAS  PubMed  Google Scholar 

  11. Andrikopoulos GK, Grammatopoulos DK, Tzeis SE, Zervou SI, Richter DJ, Zairis MN, et al. Association of the 894G > T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction. BMC Med Genet. 2008;9:43.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Abdel-Aziz TA, Mohamed RH. Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease. Mol Biol Rep. 2013;40:3065–71.

    Article  CAS  PubMed  Google Scholar 

  13. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation. 2004;110:1933–9.

    Article  CAS  PubMed  Google Scholar 

  14. Janssens S, Pokreisz P, Schoonjans L, Pellens M, Vermeersch P, Tjwa M, et al. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res. 2004;94:1256–62.

    Article  CAS  PubMed  Google Scholar 

  15. Smith Jr RS, Agata J, Xia CF, Chao L, Chao J. Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. Life Sci. 2005;76:2457–71.

    Article  CAS  PubMed  Google Scholar 

  16. Chen LL, Yin H, Huang J. Inhibition of TGF-beta1 signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through angiogenesis and reduction of apoptosis. Cardiovasc Pathol. 2007;16:221–30.

    Article  CAS  PubMed  Google Scholar 

  17. Shi CZ, Zhang XP, Lv ZW, Zhang HL, Xu JZ, Yin ZF, et al. Adipose tissue-derived stem cells embedded with eNOS restore cardiac function in acute myocardial infarction model. Int J Cardiol. 2012;154:2–8.

    Article  PubMed  Google Scholar 

  18. Janeczek A, Zimna A, Rozwadowska N, Fraczek M, Kucharzewska P, Rucinski M, et al. Genetically modified human myoblasts with eNOS may improve regenerative ability of myogenic stem cells to infarcted heart. Kardiol Pol. 2013;71:1048–58.

    Article  PubMed  Google Scholar 

  19. Chen Q, Varga M, Wang X, Haddad DJ, An S, Medzikovic L, et al. Overexpression of nitric oxide synthase restores circulating angiogenic cell function in patients with coronary artery disease: implications for autologous cell therapy for myocardial infarction. J Am Heart Assoc. 2016;5

  20. Gawronska-Kozak B, Manuel JA, Prpic V. Ear mesenchymal stem cells (EMSC) can differentiate into spontaneously contracting muscle cells. J Cell Biochem. 2007;102:122–35.

    Article  CAS  PubMed  Google Scholar 

  21. Scott MA, Nguyen VT, Levi B, James AW. Current methods of adipogenic differentiation of mesenchymal stem cells. Stem Cells Dev. 2011;20:1793–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Guo J, Duckles SP, Weiss JH, Li X, Krause DN. 17beta-estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion. Free Radic Biol Med. 2012;52:2151–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Litwin SE, Katz SE, Morgan JP, Douglas PS. Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation. 1994;89:345–54.

    Article  CAS  PubMed  Google Scholar 

  24. Chen LL, Zhu TB, Yin H, Huang J, Wang LS, Cao KJ, et al. Inhibition of MAPK signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through reduction of inflammation. Mol Biol Rep. 2010;37:3067–72.

    Article  CAS  PubMed  Google Scholar 

  25. Chiu RC, Zibaitis A, Kao RL. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann Thorac Surg. 1995;60:12–8.

    Article  CAS  PubMed  Google Scholar 

  26. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002;73:1919–25. discussion 26

    Article  PubMed  Google Scholar 

  27. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92–5.

    Article  PubMed  Google Scholar 

  28. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005;102:11474–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lim SY, Kim YS, Ahn Y, Jeong MH, Hong MH, Joo SY, et al. The effects of mesenchymal stem cells transduced with Akt in a porcine myocardial infarction model. Cardiovasc Res. 2006;70:530–42.

    Article  CAS  PubMed  Google Scholar 

  30. Sun L, Cui M, Wang Z, Feng X, Mao J, Chen P, et al. Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction. Biochem Biophys Res Commun. 2007;357:779–84.

    Article  CAS  PubMed  Google Scholar 

  31. Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, et al. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther. 2008;16:571–9.

    Article  CAS  PubMed  Google Scholar 

  32. Tang J, Wang J, Yang J, Kong X, Zheng F, Guo L, et al. Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. Eur J Cardiothorac Surg. 2009;36:644–50.

    Article  PubMed  Google Scholar 

  33. Noel D, Caton D, Roche S, Bony C, Lehmann S, Casteilla L, et al. Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials. Exp Cell Res. 2008;314:1575–84.

    Article  CAS  PubMed  Google Scholar 

  34. Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013;84:213–22.

    Article  PubMed  Google Scholar 

  35. Klinker MW, Wei CH. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J Stem Cells. 2015;7:556–67.

    Article  PubMed  PubMed Central  Google Scholar 

  36. MacFarlane RJ, Graham SM, Davies PS, Korres N, Tsouchnica H, Heliotis M, et al. Anti-inflammatory role and immunomodulation of mesenchymal stem cells in systemic joint diseases: potential for treatment. Expert Opin Ther Targets. 2013;17:243–54.

    Article  CAS  PubMed  Google Scholar 

  37. Zeira O, Asiag N, Aralla M, Ghezzi E, Pettinari L, Martinelli L, et al. Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings. J Neuroinflammation. 2015;12:181.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Dudzinski DM, Michel T. Life history of eNOS: partners and pathways. Cardiovasc Res. 2007;75:247–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007;56:1175–86.

    Article  CAS  PubMed  Google Scholar 

  40. Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther. 2008;10:223.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–36.

    Article  CAS  PubMed  Google Scholar 

  42. Smart N, Bollini S, Dube KN, Vieira JM, Zhou B, Davidson S, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474:640–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China

    Leilei Chen, Yuan Zhang, Liangliang Tao, Zhijian Yang & Liansheng Wang

Authors
  1. Leilei Chen
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  2. Yuan Zhang
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  3. Liangliang Tao
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  4. Zhijian Yang
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Corresponding author

Correspondence to Leilei Chen.

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The authors declare that they have no conflict of interest.

Research Involving Animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Leilei Chen and Yuan Zhang contributed equally to this paper.

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Chen, L., Zhang, Y., Tao, L. et al. Mesenchymal Stem Cells with eNOS Over-Expression Enhance Cardiac Repair in Rats with Myocardial Infarction. Cardiovasc Drugs Ther 31, 9–18 (2017). https://doi.org/10.1007/s10557-016-6704-z

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  • DOI: https://doi.org/10.1007/s10557-016-6704-z

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