Skip to main content
Log in

Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs

  • Article
  • Published:
Science in China Series C: Life Sciences Aims and scope Submit manuscript

Abstract

Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adenovirus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we established a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were randomly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Houser F, Culler S D, Becker E R, et al. A retrospective study of 6,671 patients comparing coronary stenting and balloon angioplasty. J Invasive Cardiol, 2000, 12: 354–362, 10904442

    Google Scholar 

  2. Horvath K A. Transmyocardial laser revascularization in the treatment of myocardial ischemia. J Card Surg, 2000, 15: 271–277, 11758063, 1:STN:280:DC%2BD38%2FjtVKntw%3D%3D, 10.1111/j.1540-8191.2000.tb01289.x

    Article  CAS  Google Scholar 

  3. Su H, Lu R, Kan Y W. Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc Natl Acad Sci USA, 2000, 97: 13801–13806, 11095751, 10.1073/pnas.250488097, 1:CAS:528:DC%2BD3cXoslyns7Y%3D

    Article  CAS  Google Scholar 

  4. Udelson J E, Dilsizian V, Laham R J, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation, 2000, 102: 1605–1610, 11015335, 1:CAS:528:DC%2BD3cXnsVClsLk%3D

    Article  CAS  Google Scholar 

  5. Funatsu T, Sawa Y, Ohtake S, et al. Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor. J Thorac Cardiovasc Surg, 2002, 124: 1099–1105, 12447174, 10.1067/mtc.2002.123809, 1:CAS:528:DC%2BD38Xpslemtr8%3D

    Article  CAS  Google Scholar 

  6. Furlong R A. The biology of hepatocyte growth factor/scatter factor. Bioessays, 1992, 14: 613–617, 1365917, 10.1002/bies.950140908, 1:CAS:528:DyaK3sXlt1GgtA%3D%3D

    Article  CAS  Google Scholar 

  7. Sengupta S, Sellers L A, Li R C, et al. Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis. Circulation, 2003, 107: 2955–2961, 12782568, 10.1161/01.CIR.0000077501.19266.E5

    Article  Google Scholar 

  8. Duan H F, Wu C T, Lu Y, et al. Sphingosine kinase activation regulates hepatocyte growth factor induced migration of endothelial cells. Exp Cell Res, 2004, 298(2): 593–601, 15265705, 10.1016/j.yexcr.2004.04.049, 1:CAS:528:DC%2BD2cXlvVWht7c%3D

    Article  CAS  Google Scholar 

  9. Chen X H, Minatoguchi S, Kosai K, et al. In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions. J Card Fail, 2007, 13: 874–883, 18068622, 10.1016/j.cardfail.2007.07.004, 1:CAS:528:DC%2BD2sXhsVWjur3J

    Article  CAS  Google Scholar 

  10. Ryugo M, Sawa Y, Ono M, et al. Myocardial protective effect of human recombinant hepatocyte growth factor for prolonged heart graft preservation in rats. Transplantation, 2004, 78: 1153–1158, 15502712, 10.1097/01.TP.0000134975.86867.F5, 1:CAS:528:DC%2BD2cXovVGis7Y%3D

    Article  CAS  Google Scholar 

  11. Yasuda S, Goto Y, Baba T, et al. Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function. J Am Coll Cardiol, 2000, 36: 115–121, 10898422, 10.1016/S0735-1097(00)00675-6, 1:CAS:528:DC%2BD3cXlsFGgs7g%3D

    Article  CAS  Google Scholar 

  12. Suzuki H, Murakami M, Shoji M, et al. Hepatocyte growth factor and vascular endothelial growth factor in ischaemic heart disease. Coron Artery Dis, 2003, 14: 301–307, 12826929, 10.1097/00019501-200306000-00005

    Google Scholar 

  13. Nakamura T, Mizuno S, Matsumoto K, et al. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest, 2000, 106: 1511–1519, 11120758, 10.1172/JCI10226, 1:CAS:528:DC%2BD3cXovFagtbk%3D

    Article  CAS  Google Scholar 

  14. Jin H, Wyss J M, Yang R, et al. The therapeutic potential of hepatocyte growth factor for myocardial infarction and heart failure. Curr Pharm Des, 2004, 10: 2525–2533, 15320761, 10.2174/1381612043383863, 1:CAS:528:DC%2BD2cXlslWjtr4%3D

    Article  CAS  Google Scholar 

  15. Duan H F, Wu C T, Wu D L, et al. Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther, 2003, 8: 467–474, 12946320, 10.1016/S1525-0016(03)00186-2, 1:CAS:528:DC%2BD3sXms1yisrs%3D

    Article  CAS  Google Scholar 

  16. Azuma J, Taniyama Y, Takeya Y, et al. Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Ther, 2006, 13: 1206–1213, 16625244, 10.1038/sj.gt.3302740, 1:CAS:528:DC%2BD28Xnsl2hu7w%3D

    Article  CAS  Google Scholar 

  17. Jayasankar V, Woo Y J, Pirolli T J, et al. Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg, 2005, 20: 93–101, 15673421, 10.1111/j.0886-0440.2005.200373.x

    Article  Google Scholar 

  18. Li Y, Takemura G, Kosai K, et al. Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice. Circulation, 2003, 107: 2499–2506, 12695295, 10.1161/01.CIR.0000065579.19126.B8, 1:CAS:528:DC%2BD3sXjs1antLo%3D

    Article  CAS  Google Scholar 

  19. Ahmet I, Sawa Y, Yamaguchi T, et al. Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thorac Surg, 2003, 75: 1283–1287, 12683576, 10.1016/S0003-4975(02)04677-5

    Article  Google Scholar 

  20. Roth D M, Maruoka Y, Rogers J, et al. Development of coronary collateral circulation in left circumflex Ameroid-occluded swine myocardium. Am J Physiol, 1987, 253(5Pt2): H1279–H1288, 3318503, 1:STN:280:DyaL1c%2FnsVygug%3D%3D

    CAS  Google Scholar 

  21. Wu D L, Zhang Y R, Lao M F, et al. Therapeutic induction of angiogenesis by direct myocardial administration of an adenovirus vector encoding human hepatocyte growth factor gene and its safety. Chin Sci Bull, 2004, 49(14): 1464–1469, 10.1360/04wc0161, 1:CAS:528:DC%2BD2cXnvFKrur4%3D

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun Huang.

Additional information

Contributed equally to this work

Supported by National “863” Programme (Grant Nos. 2003AA216080 and 2007AA021007)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, B., Zhang, Y., Zhao, Z. et al. Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs. SCI CHINA SER C 51, 537–543 (2008). https://doi.org/10.1007/s11427-008-0073-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-008-0073-1

Keywords

Navigation