Skip to main content

Advertisement

SpringerLink
Log in

Novel therapy for myocardial infarction: can HGF/Met be beneficial?

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Myocardial infarction (MI) is a leading cause of hospitalization worldwide. A recently developed strategy to improve the management of MI is based on the use of growth factors which are able to enhance the intrinsic capacity of the heart to repair itself or regenerate after damage. Among others, hepatocyte growth factor (HGF) has been proposed as a modulator of cardiac repair of damage due to the pleiotropic effects elicited by Met receptor stimulation. In this review we describe the mechanistic basis for autocrine and paracrine protection of HGF in the injured heart. We also analyse the role of HGF/Met in stem cell maintenance and in stem cell therapies for MI. Finally, we summarize the most significant results on the use of HGF in experimental models of heart injury and discuss the potential of the molecule for treating ischaemic heart disease in humans.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fenton D (2010) Myocardial infarction. eMedicine. http://www.emedicine.com/EMERG/topic327.htm

  2. Frangogiannis NG (2006) Targeting the inflammatory response in healing myocardial infarcts. Curr Med Chem 13:1877–1893

    PubMed  CAS  Google Scholar 

  3. Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascirnbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, LeCapitaine N, Cascapera S, Beltrami AP, D’Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P (2007) Human cardiac stem cells. Proc Natl Acad Sci U S A 104:14068–14073

    PubMed  CAS  Google Scholar 

  4. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776

    PubMed  CAS  Google Scholar 

  5. Matsuura K, Nagai T, Nishigaki N, Oyama T, Nishi J, Wada H, Sano M, Toko H, Akazawa H, Sato T, Nakaya H, Kasanuki H, Komuro I (2004) Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem 279:11384–11391

    PubMed  CAS  Google Scholar 

  6. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 100:12313–12318

    PubMed  CAS  Google Scholar 

  7. Gnecchi M, Zhang ZP, Ni AG, Dzau VJ (2008) Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103:1204–1219

    PubMed  CAS  Google Scholar 

  8. Jin HK, Wyss JM, Yang RH, Schwall R (2004) The therapeutic potential of hepatocyte growth factor for myocardial infarction and heart failure. Curr Pharm Des 10:2525–2533

    PubMed  CAS  Google Scholar 

  9. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S (1989) Molecular-cloning and expression of human hepatocyte growth-factor. Nature 342:440–443

    PubMed  CAS  Google Scholar 

  10. Park M, Dean M, Cooper CS, Schmidt M, O’Brien SJ, Blair DG, Vande Woude GF (1986) Mechanism of met oncogene activation. Cell 45:895–904

    PubMed  CAS  Google Scholar 

  11. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    PubMed  CAS  Google Scholar 

  12. Comoglio PM, Trusolino L (2002) Invasive growth: from development to metastasis. J Clin Invest 109:857–862

    PubMed  CAS  Google Scholar 

  13. Rappolee DA, Iyer A, Patel Y (1996) Hepatocyte growth factor and its receptor are expressed in cardiac myocytes during early cardiogenesis. Circ Res 78:1028–1036

    PubMed  CAS  Google Scholar 

  14. Matsumori A, Furukawa Y, Hashimoto T, Ono K, Shioi T, Okada M, Iwasaki A, Nishio R, Sasayama S (1996) Increased circulating hepatocyte growth factor in the early stage of acute myocardial infarction. Biochem Biophys Res Commun 221:391–395

    PubMed  CAS  Google Scholar 

  15. Ueda H, Nakamura T, Matsumoto K, Sawa Y, Matsuda H, Nakamura T (2001) A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats. Cardiovasc Res 51:41–50

    PubMed  CAS  Google Scholar 

  16. Matsumoto K, Nakamura T (1996) Emerging multipotent aspects of hepatocyte growth factor. J Biochem 119:591–600

    PubMed  CAS  Google Scholar 

  17. Fujii K, Ishimaru F, Kozuka T, Matsuo K, Nakase K, Kataoka I, Tabayashi T, Shinagawa K, Ikeda K, Harada M, Tanimoto M (2004) Elevation of serum hepatocyte growth factor during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization. Br J Haematol 124:190–194

    PubMed  CAS  Google Scholar 

  18. Boccaccio C, Gaudino G, Gambarotta G, Galimi F, Comoglio PM (1994) Hepatocyte growth-factor (Hgf) receptor expression is inducible and is part of the delayed-early response to Hgf. J Biol Chem 269:12846–12851

    PubMed  CAS  Google Scholar 

  19. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361

    PubMed  Google Scholar 

  20. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S (1997) Enhanced expression of hepatocyte growth factor c-Met by myocardial ischemia and reperfusion in a rat model. Circulation 95:2552–2558

    PubMed  CAS  Google Scholar 

  21. Konopka A, Janas J, Piotrowski W, Stepinska J (2010) Hepatocyte growth factor – a new marker for prognosis in acute coronary syndrome. Growth Factors 28:75–81

    PubMed  CAS  Google Scholar 

  22. Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H, Nakamura T (2000) Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest 106:1511–1519

    PubMed  CAS  Google Scholar 

  23. Funatsu T, Sawa Y, Ohtake S, Takahashi T, Matsumiya G, Matsuura N, Nakamura T, Matsuda H (2002) Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor. J Thorac Cardiovasc Surg 124:1099–1105

    PubMed  CAS  Google Scholar 

  24. Jayasankar V, Woo YJ, Bish LT, Pirolli TJ, Chatterjee S, Berry MF, Burdick J, Gardner TJ, Sweeney HL (2003) Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 108(Suppl 1):II230–II236

    PubMed  Google Scholar 

  25. Li YW, Takemura G, Kosai K, Yuge K, Nagano S, Esaki M, Goto K, Takahashi T, Hayakawa K, Koda M, Kawase Y, Maruyama R, Okada H, Minatoguchi S, Mizuguchi H, Fujiwara T, Fujiwara H (2003) Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice. Circulation 107:2499–2506

    PubMed  CAS  Google Scholar 

  26. Miyagawa S, Sawa Y, Taketani S, Kawaguchi N, Nakamura T, Matsuura N, Matsuda F (2002) Myocardial regeneration therapy for heart failure – hepatocyte growth factor enhances the effect of cellular cardiomyoplasty. Circulation 105:2556–2561

    PubMed  CAS  Google Scholar 

  27. Scarabelli TM, Gottlieb RA (2004) Functional and clinical repercussions of myocyte apoptosis in the multifaceted damage by ischemia/reperfusion injury: old and new concepts after 10 years of contributions. Cell Death Differ 11:S144–S152

    PubMed  CAS  Google Scholar 

  28. Kitta K, Day RM, Ikeda T, Suzuki YJ (2001) Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis. Free Radic Biol Med 31:902–910

    PubMed  CAS  Google Scholar 

  29. Wang YG, Ahmad N, Wani MA, Ashraf M (2004) Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis. J Mol Cell Cardiol 37:1041–1052

    PubMed  CAS  Google Scholar 

  30. Iwasaki M, Adachi Y, Nishiue T, Minamino K, Suzuki Y, Zhang YM, Nakano KJ, Koike Y, Wang JF, Mukaide H, Taketani S, Yuasa F, Tsubouchi H, Gohda E, Iwasaka T, Ikehara S (2005) Hepatocyte growth factor delivered by ultrasound-mediated destruction of microbubbles induces proliferation of cardiomyocytes and amelioration of left ventricular contractile function in doxorubicin-induced cardiomyopathy. Stem Cells 23:1589–1597

    PubMed  Google Scholar 

  31. Esaki M, Takemura G, Kosai KI, Takahashi T, Miyata S, Li LH, Goto K, Maruyama R, Okada H, Kanamori H, Ogino A, Ushikoshi H, Minatoguchi S, Fujiwara T, Fujiwara H (2008) Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294:H1048–H1057

    PubMed  CAS  Google Scholar 

  32. Pietronave S, Forte G, Locarno D, Merlin S, Zamperone A, Nicotra G, Isidoro C, Di Nardo P, Prat M (2010) Agonist monoclonal antibodies against HGF receptor protect cardiac muscle cells from apoptosis. Am J Physiol Heart Circ Physiol 298:H1155–H1165

    PubMed  CAS  Google Scholar 

  33. Liu YH (1999) Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol Renal Physiol 277:F624–F633

    CAS  Google Scholar 

  34. Cao XB, Littlejohn J, Rodarte C, Zhang LD, Martino B, Rascoe P, Hamid K, Jupiter D, Smythe WR (2009) Up-regulation of Bcl-xl by hepatocyte growth factor in human mesothelioma cells involves ETS transcription factors. Am J Pathol 175:2207–2216

    PubMed  CAS  Google Scholar 

  35. Kitta K, Day RM, Kim Y, Torregroza I, Evans T, Suzuki YJ (2003) Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells. J Biol Chem 278:4705–4712

    PubMed  CAS  Google Scholar 

  36. Bussolino F, Direnzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth-factor is a potent angiogenic factor which stimulates endothelial-cell motility and growth. J Cell Biol 119:629–641

    PubMed  CAS  Google Scholar 

  37. Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P, Rosen EM (1993) Scatter factor induces blood-vessel formation in vivo. Proc Natl Acad Sci U S A 90:1937–1941

    PubMed  CAS  Google Scholar 

  38. Ding SL, Merkulova-Rainon T, Han ZC, Tobelem G (2003) HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101:4816–4822

    PubMed  CAS  Google Scholar 

  39. Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1999) Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33:1379–1384

    PubMed  CAS  Google Scholar 

  40. Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higaki J, Ogihara T (2000) Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Ther 7:417–427

    PubMed  CAS  Google Scholar 

  41. Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taiji M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1999) Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease – downregulation of HGF in response to hypoxia in vascular cells. Circulation 100:301–308

    CAS  Google Scholar 

  42. Taniyama Y, Morishita R, Hiraoka K, Aoki M, Nakagami H, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T (2001) Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model – molecular mechanisms of delayed angiogenesis in diabetes. Circulation 104:2344–2350

    PubMed  CAS  Google Scholar 

  43. Nakamura Y, Morishita R, Higaki J, Kida I, Aoki M, Moriguchi A, Yamada K, Hayashi S, Yo Y, Nakano H, Matsumoto K, Nakamura T, Ogihara T (1996) Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor. J Hypertens 14:1067–1072

    PubMed  CAS  Google Scholar 

  44. Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF, Isner JM (2000) Left ventricular electromechanical mapping to assess efficacy of phVEGP(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 102:965–974

    PubMed  CAS  Google Scholar 

  45. Horiguchi N, Takayama H, Toyoda M, Otsuka T, Fukusato T, Merlino G, Takagi H, Mori M (2002) Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine. Oncogene 21:1791–1799

    PubMed  CAS  Google Scholar 

  46. Saucier C, Khoury H, Lai KMV, Peschard P, Dankort D, Naujokas MA, Holash J, Yancopoulos GD, Muller WJ, Pawson T, Park M (2004) The Shc adaptor protein is critical for VEGF induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis. Proc Natl Acad Sci U S A 101:2345–2350

    PubMed  CAS  Google Scholar 

  47. Van Belle E, Witzenbichler B, Chen DH, Silver M, Chang L, Schwall R, Isner JM (1998) Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor – the case for paracrine amplification of angiogenesis. Circulation 97:381–390

    PubMed  Google Scholar 

  48. Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR (1999) Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest 79:427–438

    PubMed  CAS  Google Scholar 

  49. Kaposi-Novak P, Lee JS, Gomez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595

    PubMed  CAS  Google Scholar 

  50. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514

    PubMed  CAS  Google Scholar 

  51. Min JK, Lee YM, Kim JH, Kim YM, Kim SW, Lee SY, Gho YS, Oh GT, Kwon YG (2005) Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappa B pathway. Circ Res 96:300–307

    PubMed  CAS  Google Scholar 

  52. Deindl E, Zaruba MM, Brunner S, Huber B, Mehl U, Assmann G, Hoefer IE, Mueller-Hoecker J, Franz WM (2006) G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J 20:956–958

    PubMed  CAS  Google Scholar 

  53. Kobayashi H, Debusk LM, Babichev YO, Dumont DJ, Lin PC (2006) Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment. Blood 108:1260–1266

    PubMed  CAS  Google Scholar 

  54. Chen XH, Minatoguchi S, Kosai K, Yuge K, Takahashi T, Arai M, Wang NY, Misao Y, Lu CJ, Onogi H, Kobayashi H, Yasuda S, Ezaki M, Ushikoshi H, Takemura G, Fujiwara T, Fujiwara H (2007) In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions. J Card Fail 13:874–883

    PubMed  CAS  Google Scholar 

  55. Nakamura T, Matsumoto K, Mizuno S, Sawa Y, Matsuda H, Nakamura T (2005) Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts. Am J Physiol Heart Circ Physiol 288:H2131–H2139

    PubMed  CAS  Google Scholar 

  56. Taniyama Y, Morishita R, Aoki M, Hiraoka K, Yamasaki K, Hashiya N, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T (2002) Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy. Hypertension 40:47–53

    PubMed  CAS  Google Scholar 

  57. Campbell SE, Katwa LC (1997) Angiotensin II stimulated expression of transforming growth factor-beta(1) in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 29:1947–1958

    PubMed  CAS  Google Scholar 

  58. Kim NN, Villarreal FJ, Printz MP, Lee AA, Dillmann WH (1995) Trophic effects of angiotensin II on neonatal rat cardiac myocytes are mediated by cardiac fibroblasts. Am J Physiol Endocrinol Metab 32:E426–E437

    Google Scholar 

  59. Lee AA, Dillmann WH, Mcculloch AD, Villarreal FJ (1995) Angiotensin-II stimulates the autocrine production of transforming growth-factor-beta-1 in adult-rat cardiac fibroblasts. J Mol Cell Cardiol 27:2347–2357

    PubMed  CAS  Google Scholar 

  60. MacKenna D, Summerour SR, Villarreal FJ (2000) Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res 46:257–263

    PubMed  CAS  Google Scholar 

  61. Villarreal FJ, Dillmann WH (1992) Cardiac hypertrophy-induced changes in messenger-RNA levels for TGF-beta-1, fibronectin, and collagen. Am J Physiol 262:H1861–H1866

    PubMed  CAS  Google Scholar 

  62. Schultz JE, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T (2002) TGF-beta 1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109:787–796

    CAS  Google Scholar 

  63. Taniyama Y, Morishita R, Nakagami H, Moriguchi A, Sakonjo H, Shokei K, Matsumoto K, Nakamura T, Higaki J, Ogihara T (2000) Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters. Circulation 102:246–252

    PubMed  CAS  Google Scholar 

  64. Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Takahashi H, Okamoto E, Fujimoto J (1999) Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med 5:226–230

    PubMed  CAS  Google Scholar 

  65. Mizuno S, Matsumoto K, Li MY, Nakamura T (2005) HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J 19:580–582

    PubMed  Google Scholar 

  66. Yang JW, Dai CS, Liu YH (2003) Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol 163:621–632

    PubMed  CAS  Google Scholar 

  67. Kobayashi E, Sasamura H, Mifune M, Shimizu-Hirota R, Kuroda M, Hayashi M, Saruta T (2003) Hepatocyte growth factor regulates proteoglycan synthesis in interstitial fibroblasts. Kidney Int 64:1179–1188

    PubMed  CAS  Google Scholar 

  68. Azuma J, Taniyama Y, Takeya Y, Iekushi K, Aoki M, Dosaka N, Matsumoto K, Nakamura T, Ogihara T, Morishita R (2006) Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Ther 13:1206–1213

    PubMed  CAS  Google Scholar 

  69. Purdie KJ, Whitley GS, Johnstone AP, Cartwright JE (2002) Hepatocyte growth factor-induced endothelial cell motility is mediated by the upregulation of inducible nitric oxide synthase expression. Cardiovasc Res 54:659–668

    PubMed  CAS  Google Scholar 

  70. Takemoto M, Egashira K, Tomita H, Usui M, Okamoto H, Kitabatake A, Shimokawa H, Sueishi K, Takeshita A (1997) Chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade – effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis. Hypertension 30:1621–1627

    PubMed  CAS  Google Scholar 

  71. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A (1998) Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 32:273–279

    PubMed  CAS  Google Scholar 

  72. Gum R, Lengyel E, Juarez J, Chen JH, Sato H, Seiki M, Boyd D (1996) Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J Biol Chem 271:10672–10680

    PubMed  CAS  Google Scholar 

  73. Nerlov C, Rorth P, Blasi F, Johnsen M (1991) Essential Ap-1 and Pea3 binding-elements in the human urokinase enhancer display cell type-specific activity. Oncogene 6:1583–1592

    PubMed  CAS  Google Scholar 

  74. Vandenbunder B, Wernert N, Queva C, Desbiens X, Stehelin D (1994) Does the transcription factor C-Ets1 take part in the regulation of angiogenesis and tumor invasion. Folia Biol Prague 40:301–313

    CAS  Google Scholar 

  75. Lewin B (1991) Oncogenic conversion by regulatory changes in transcription factors. Cell 64:303–312

    PubMed  CAS  Google Scholar 

  76. Iwasaka C, Tanaka K, Abe M, Sato Y (1996) Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. J Cell Physiol 169:522–531

    PubMed  CAS  Google Scholar 

  77. Nakano N, Moriguchi A, Morishita R, Kida I, Tomita N, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1997) Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats. Hypertension 30:1448–1454

    PubMed  CAS  Google Scholar 

  78. Nakano N, Morishita R, Moriguchi A, Nakamura Y, Hayashi S, Aoki M, Kida I, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1998) Negative regulation of local hepatocyte growth factor expression by angiotensin II and transforming growth factor-beta in blood vessels – potential role of HGF in cardiovascular disease. Hypertension 32:444–451

    PubMed  CAS  Google Scholar 

  79. Galimi F, Cottone E, Vigna E, Arena N, Boccaccio C, Giordano S, Naldini L, Comoglio PM (2001) Hepatocyte growth factor is a regulator of monocyte-macrophage function. J Immunol 166:1241–1247

    PubMed  CAS  Google Scholar 

  80. Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A, Danese S, Pessina G, Pandolfi S, Natoni F, Di Febo A, Scambia G, Manfredini R, Salati S, Ferrari S, Pierelli L, Leone G, Lemoli RM (2006) Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12(low/neg) accessory cells with dendritic-cell features. Blood 108:218–227

    PubMed  CAS  Google Scholar 

  81. Yang ZQ, Zingarelli B, Szabo C (2000) Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 101:1019–1026

    PubMed  CAS  Google Scholar 

  82. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85:E17–E24

    PubMed  CAS  Google Scholar 

  83. Mtairag E, Chollet-Martin S, Oudghiri M, Laquay N, Jacob MP, Michel JB, Feldman LJ (2001) Effects of interleukin-10 on monocyte/endothelial cell adhesion and MMP-9/TIMP-1 secretion. Cardiovasc Res 49:882–890

    Google Scholar 

  84. Smith DA, Irving SD, Sheldon J, Cole D, Kaski JC (2001) Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation 104:746–749

    PubMed  CAS  Google Scholar 

  85. Yang ZJ, Xu SL, Chen B, Zhang SL, Zhang YL, Wei W, Ma DC, Wang LS, Zhu TB, Li CJ, Wang H, Cao KJ, Gao W, Huang J, Ma WZ, Wu ZZ (2009) Hepatocyte growth factor plays a critical role in the regulation of cytokine production and induction of endothelial progenitor cell mobilization: a pilot gene therapy study in patients with coronary heart disease. Clin Exp Pharmacol Physiol 36:790–796

    PubMed  CAS  Google Scholar 

  86. Yue TL, Wang X, Sung CP, Olson B, Mckenna PJ, Gu JL, Feuerstein GZ (1994) Interleukin-8 – a mitogen and chemoattractant for vascular smooth-muscle cells. Circ Res 75:1–7

    PubMed  CAS  Google Scholar 

  87. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA, Luster AD, Luscinskas FW, Rosenzweig A (1999) MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398:718–723

    PubMed  CAS  Google Scholar 

  88. Molad Y, Haines KA, Anderson DC, Buyon JP, Cronstein BN (1994) Immunocomplexes stimulate different signaling events to chemoattractants in the neutrophil and regulate l-selectin and beta(2)-integrin expression differently. Biochem J 299:881–887

    PubMed  CAS  Google Scholar 

  89. Peveri P, Walz A, Dewald B, Baggiolini M (1988) A novel neutrophil-activating factor produced by human mononuclear phagocytes. J Exp Med 167:1547–1559

    PubMed  CAS  Google Scholar 

  90. Schroder JM, Christophers E (1989) Secretion of novel and homologous neutrophil-activating peptides by LPS-stimulated human-endothelial cells. J Immunol 142:244–251

    PubMed  CAS  Google Scholar 

  91. Watanabe K, Fukuda H, Sueda S, Funada J, Kitakaze M, Sekiya M (2001) Metabolism of hepatocyte growth factor in the heart in patients with coronary artery disease: implication for coronary arteriosclerosis. Cardiovasc Drugs Ther 15:147–153

    PubMed  CAS  Google Scholar 

  92. Futamatsu H, Suzuki J, Mizuno S, Koga N, Adachi S, Kosuge H, Maejima Y, Hirao K, Nakamura T, Isobe M (2005) Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis – a potential role for induction of T helper 2 cytokines. Circ Res 96:823–830

    PubMed  CAS  Google Scholar 

  93. Benkhoucha M, Santiago-Raber ML, Schneiter G, Chofflon M, Funakoshi H, Nakamura T, Lalive PH (2010) Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25(+)Foxp3(+) regulatory T cells. Proc Natl Acad Sci U S A 107:6424–6429

    PubMed  CAS  Google Scholar 

  94. Dallman MJ, Larsen CP, Morris PJ (1991) Cytokine gene-transcription in vascularized organ grafts – analysis using semiquantitative polymerase chain-reaction. J Exp Med 174:493–496

    PubMed  CAS  Google Scholar 

  95. Saiura A, Mataki C, Murakami T, Umetani M, Wada Y, Kohro T, Aburatani H, Harihara Y, Hamakubo T, Yamaguchi T, Hasegawa G, Naito M, Makuuchi M, Kodama T (2001) A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation 72:320–329

    PubMed  CAS  Google Scholar 

  96. Yamaura K, Ito K, Tsukioka K, Wada Y, Makiuchi A, Sakaguchi M, Akashima T, Fujimori M, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Suzuki J, Amano J, Isobe M (2004) Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation – induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation 110:1650–1657

    PubMed  CAS  Google Scholar 

  97. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA (2002) The post-natal heart contains a myocardial stem cell population. FEBS Lett 530:239–243

    PubMed  CAS  Google Scholar 

  98. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen YH, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JXJ, Evans S, Chien KR (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653

    PubMed  CAS  Google Scholar 

  99. Martin CM, Meeson AP, Robertson SM, Hawke TJ, Richardson JA, Bates S, Goetsch SC, Gallardo TD, Garry DJ (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265:262–275

    PubMed  CAS  Google Scholar 

  100. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MVG, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95:911–921

    PubMed  CAS  Google Scholar 

  101. Torella D, Ellison GM, Mendez-Ferrer S, Ibanez B, Nadal-Ginard B (2006) Resident human cardiac stem cells: role in cardiac cellular homeostasis and potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med 3:S8–S13

    PubMed  CAS  Google Scholar 

  102. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P (2002) Chimerism of the transplanted heart. N Engl J Med 346:5–15

    PubMed  Google Scholar 

  103. Parmacek MS, Epstein JA (2005) Pursuing cardiac progenitors: regeneration redux. Cell 120:295–298

    PubMed  CAS  Google Scholar 

  104. Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85:1373–1416

    PubMed  CAS  Google Scholar 

  105. Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda T, Chimenti S, Baker M, Limana F, Nurzynska D, Torella D, Rotatori F, Rastaldo R, Musso E, Quaini F, Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res 97:663–673

    PubMed  CAS  Google Scholar 

  106. Stastna M, Abraham MR, Van Eyk JE (2009) Cardiac stem/progenitor cells, secreted proteins, and proteomics. FEBS Lett 583:1800–1807

    PubMed  CAS  Google Scholar 

  107. Stastna M, Chimenti I, Marban E, Van Eyk JE (2010) Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes. Proteomics 10:245–253

    PubMed  CAS  Google Scholar 

  108. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, Marban E (2010) Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 106:U304–U971

    Google Scholar 

  109. Linke A, Muller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Bohm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J, Anversa P (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 102:8966–8971

    PubMed  CAS  Google Scholar 

  110. Rota M, Padin-Iruegas ME, Misao Y, De Angelis A, Maestroni S, Ferreira-Martins J, Fiumana E, Rastaldo R, Arcarese ML, Mitchell TS, Boni A, Bolli R, Urbanek K, Hosoda T, Anversa P, Leri A, Kajstura J (2008) Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 103:107–116

    PubMed  CAS  Google Scholar 

  111. Andermarcher E, Surani MA, Gherardi E (1996) Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis. Dev Genet 18:254–266

    PubMed  CAS  Google Scholar 

  112. Song WM, Majka SM, McGuire PG (1999) Hepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression. Dev Dyn 214:92–100

    PubMed  CAS  Google Scholar 

  113. Romano LA, Runyan RB (2000) Slug is an essential target of TGF beta 2 signaling in the developing chicken heart. Dev Biol 223:91–102

    PubMed  CAS  Google Scholar 

  114. Domian IJ, Chiravuri M, van der Meer P, Feinberg AW, Shi X, Shao Y, Wu SM, Parker KK, Chien KR (2009) Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326:426–429

    PubMed  CAS  Google Scholar 

  115. Cai CL, Martin JC, Sun YF, Cui L, Wang LC, Ouyang K, Yang L, Bu L, Liang XQ, Zhang XX, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM (2008) A myocardial lineage derives from Tbx18 epicardial cells. Nature 454:1U4–1U104

    Google Scholar 

  116. Muñoz-Chápuli R, Pérez-Pomares JM, Macías D, García-Garrido L, Carmona R, González-Iriarte M (2001) The epicardium as a source of mesenchyme for the developing heart. Ital J Anat Embryol 106(2 Suppl 1):187–196

    PubMed  Google Scholar 

  117. Winter EM, Gittenberger-de Groot AC (2007) Epicardium-derived cells in cardiogenesis and cardiac regeneration. Cell Mol Life Sci 64:692–703

    PubMed  CAS  Google Scholar 

  118. Perez-Pomares JM, Carmona R, Gonzalez-Iriarte M, Atencia G, Wessels A, Munoz-Chapuli R (2002) Origin of coronary endothelial cells from epicardial mesothelium in avian embryos. Int J Dev Biol 46:1005–1013

    PubMed  CAS  Google Scholar 

  119. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, Rivera-Feliciano J, Jiang DW, von Gise A, Ikeda S, Chien KR, Pu WT (2008) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454:1U5–1U109

    Google Scholar 

  120. Reese DE, Mikawa T, Bader DM (2002) Development of the coronary vessel system. Circ Res 91:761–768

    PubMed  CAS  Google Scholar 

  121. Wada AM, Smith TK, Osler ME, Reese DE, Bader DM (2003) Epicardial/mesothelial cell line retains vasculogenic potential of embryonic epicardium. Circ Res 92:525–531

    PubMed  CAS  Google Scholar 

  122. Smart N, Risebro CA, Melville AAD, Moses K, Schwartz RJ, Chien KR, Riley PR (2007) Thymosin beta 4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445:177–182

    PubMed  CAS  Google Scholar 

  123. Tallini YN, Greene KS, Craven M, Spealman A, Breitbach M, Smith J, Fisher PJ, Steffey M, Hesse M, Doran RM, Woods A, Singh B, Yen A, Fleischmann BK, Kotlikoff MI (2009) c-Kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci U S A 106:1808–1813

    PubMed  CAS  Google Scholar 

  124. Limana F, Zacheo A, Mocini D, Mangoni A, Borsellino G, Diamantini A, De Mori R, Battistini L, Vigna E, Santini M, Loiaconi V, Pompilio G, Germani A, Capogrossi MC (2007) Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101:1255–1265

    PubMed  CAS  Google Scholar 

  125. Limana F, Bertolami C, Mangoni A, Di Carlo A, Avitabile D, Mocini D, Iannelli P, De Mori R, Marchetti C, Pozzoli O, Gentili C, Zacheo A, Germani A, Capogrossi MC (2010) Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid. J Mol Cell Cardiol 48:609–618

    PubMed  CAS  Google Scholar 

  126. Roggia C, Ukena C, Bohm M, Kilter H (2007) Hepatocyte growth factor (HGF) enhances cardiac commitment of differentiating embryonic stem cells by activating P13 kinase. Exp Cell Res 313:921–930

    PubMed  CAS  Google Scholar 

  127. Yoon YS, Wecker A, Heyd L, Park JS, Tkebuchava T, Kusano K, Hanley A, Scadova H, Qin GJ, Cha DH, Johnson KL, Aikawa R, Asahara T, Losordo DW (2005) Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest 115:326–338

    PubMed  CAS  Google Scholar 

  128. Rehman J, Li JL, Orschell CM, March KL (2003) Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169

    PubMed  Google Scholar 

  129. Cho HJ, Lee N, Lee JY, Choi YJ, Li M, Wecker A, Jeong JO, Curry C, Qin G, Yoon YS (2007) Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart. J Exp Med 204:3257–3269

    PubMed  CAS  Google Scholar 

  130. Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S (2005) Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol 39:733–742

    PubMed  CAS  Google Scholar 

  131. Neuss S, Becher E, Woltje M, Tietze L, Jahnen-Dechent W (2004) Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells 22:405–414

    PubMed  CAS  Google Scholar 

  132. Rosova I, Dao M, Capoccia B, Link D, Nolta JA (2008) Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26:2173–2182

    PubMed  CAS  Google Scholar 

  133. Cai L, Johnstone BH, Cook TG, Liang Z, Traktuev D, Cornetta K, Ingram DA, Rosen ED, Marcha KL (2007) Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. Stem Cells 25:3234–3243

    PubMed  CAS  Google Scholar 

  134. Rehman J, Traktuev D, Li JL, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 109:1292–1298

    PubMed  Google Scholar 

  135. Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG (2005) Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension 46:7–18

    PubMed  CAS  Google Scholar 

  136. Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109:1543–1549

    PubMed  CAS  Google Scholar 

  137. Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P, Sussman MA (2006) Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res 99:381–388

    PubMed  CAS  Google Scholar 

  138. Guo YH, He JG, Wu JL, Yang L, Dai SM, Tan XY, Liang LR (2008) Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis. Arch Med Res 39:179–188

    PubMed  CAS  Google Scholar 

  139. Mirotsou M, Zhang ZY, Deb A, Zhang LN, Gnecchi M, Noiseux N, Mu H, Pachori A, Dzau V (2007) Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A 104:1643–1648

    PubMed  CAS  Google Scholar 

  140. Gnecchi M, He HM, Noiseux N, Liang OD, Zhang LM, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669

    PubMed  CAS  Google Scholar 

  141. Dhein S, Garbade J, Rouabah D, Abraham G, Ungemach FR, Schneider K, Ullmann C, Aupperle H, Gummert JF, Mohr FW (2006) Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure. J Cardiothorac Surg 1:17

    PubMed  Google Scholar 

  142. Ohnishi S, Yasuda T, Kitamura S, Nagaya N (2007) Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells. Stem Cells 25:1166–1177

    PubMed  CAS  Google Scholar 

  143. Tang JM, Wang JN, Guo LY, Kong X, Yang JY, Zheng F, Zhang L, Huang YZ (2010) Mesenchymal stem cells modified with stromal cell-derived factor 1 alpha improve cardiac remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction. Mol Cells 29:9–19

    PubMed  Google Scholar 

  144. Sánchez PL, San Román JA, Villa A, Fernández ME, Fernández-Avilés F (2006) Contemplating the bright future of stem cell therapy for cardiovascular disease. Nat Clin Pract Cardiovasc Med 3:S138–S151

    PubMed  Google Scholar 

  145. Minasi MG, Riminucci M, De Angelis L, Borello U, Berarducci B, Innocenzi A, Caprioli A, Sirabella D, Baiocchi M, De Maria R, Boratto R, Jaffredo T, Broccoli V, Bianco P, Cossu G (2002) The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129:2773–2784

    PubMed  CAS  Google Scholar 

  146. Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F, Chimenti S, Cusella G, Dejana E, Cossu G, Latini R (2005) Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular mechanisms – a comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arter Thromb Vasc Biol 25:692–697

    CAS  Google Scholar 

  147. Imhof BA, Aurrand-Lions M (2004) Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 4:432–444

    PubMed  CAS  Google Scholar 

  148. Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V, Fiaccavento R, Carotenuto F, De Vito P, Baldini PM, Prat M, Di Nardo P (2006) Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation. Stem Cells 24:23–33

    PubMed  CAS  Google Scholar 

  149. Kucia M, Dawn B, Hunt G, Guo YR, Wysoczynski M, Majka M, Ratajczak J, Rezzoug F, Ildstad ST, Bolli R, Ratajczak MZ (2004) Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction. Circ Res 95:1191–1199

    PubMed  CAS  Google Scholar 

  150. Lataillade JJ, Domenech J, Bousse-Kerdiles MC (2004) Stromal cell-derived factor-1 (SDF-1)/CXCR4 couple plays multiple roles on haematopoietic progenitors at the border between the old cytokine and new chemokine worlds: survival, cell cycling and trafficking. Eur Cytokine Netw 15:177–188

    PubMed  CAS  Google Scholar 

  151. Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ (2004) Stromal cell-derived factor-1 alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110:3300–3305

    PubMed  Google Scholar 

  152. Dentelli P, Rosso A, Balsamo A, Benedetto SC, Zeoli A, Pegoraro M, Camussi G, Pegoraro L, Brizzi MF (2007) C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium. Blood 109:4264–4271

    PubMed  CAS  Google Scholar 

  153. Petit I, Jin D, Rafii S (2007) The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol 28:299–307

    PubMed  CAS  Google Scholar 

  154. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    PubMed  CAS  Google Scholar 

  155. Tacchini L, Dansi P, Matteucci E, Desiderio MA (2001) Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 22:1363–1371

    PubMed  CAS  Google Scholar 

  156. Maroni P, Bendinelli P, Matteucci E, Desiderio MA (2007) HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappa B. Carcinogenesis 28:267–279

    PubMed  CAS  Google Scholar 

  157. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189

    PubMed  CAS  Google Scholar 

  158. Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24:1254–1264

    PubMed  CAS  Google Scholar 

  159. Vasyutina E, Stebler J, Brand-Saberi B, Schulz S, Raz E, Birchmeier C (2005) CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Gene Dev 19:2187–2198

    PubMed  CAS  Google Scholar 

  160. Ratajczak MZ, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S, Janowska-Wieczorek A (2003) Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells 21:363–371

    PubMed  CAS  Google Scholar 

  161. Ahmet I, Sawa Y, Yamaguchi T, Matsuda H (2003) Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thorac Surg 75:1283–1287

    PubMed  Google Scholar 

  162. Jayasankar V, Woo YJ, Pirolli TJ, Bish LT, Berry MF, Burdick J, Gardner TJ, Sweeney HL (2005) Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg 20:93–101

    PubMed  Google Scholar 

  163. Wang W, Yang ZJ, Ma DC, Wang LS, Xu SL, Zhang YR, Cao KJ, Zhang FM, Ma WZ (2006) Induction of collateral artery growth and improvement of post-infarct heart function by hepatocyte growth factor gene transfer. Acta Pharmacol Sin 27:555–560

    PubMed  CAS  Google Scholar 

  164. Yuan B, Zhang YR, Zhao Z, Wu DL, Yuan LZ, Wu B, Wang LS, Huang J (2008) Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs. Sci China Ser C 51:537–543

    Google Scholar 

  165. Yang ZJ, Ma DC, Wang W, Xu SL, Zhang YQ, Chen B, Zhou F, Zhu TB, Wang LS, Xu ZQ, Zhang FM, Cao KJ, Ma WZ (2006) Experimental study of bone marrow-derived mesenchymal stem cells combined with hepatocyte growth factor transplantation via noninfarct-relative artery in acute myocardial infarction. Gene Ther 13:1564–1568

    PubMed  CAS  Google Scholar 

  166. Yuan B, Zhao Z, Zhang YR, Wu CT, Jin WG, Zhao S, Wang W, Zhang YY, Zhu XL, Wang LS, Huang J (2008) Short-term safety and curative effect of recombinant adenovirus carrying hepatocyte growth factor gene on ischemic cardiac disease. In Vivo 22:629–632

    PubMed  CAS  Google Scholar 

  167. Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, Zhu TB, Li CJ, Wang H, Huang J, Cao KJ, Ma WZ, Wu B, Wang LS, Wu CT (2009) Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease. Mol Biol Rep 36:1323–1329

    PubMed  CAS  Google Scholar 

  168. Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T (2004) Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 44:203–209

    PubMed  CAS  Google Scholar 

  169. McKinnon H, Gherardi E, Reidy M, Bowyer D (2006) Hepatocyte growth factor/scatter factor and MET are involved in arterial repair and atherogenesis. Am J Pathol 168:340–348

    PubMed  CAS  Google Scholar 

  170. Lamblin N, Susen S, Dagorn J, Mouquet F, Jude M, Van Belle E, Bauters C, de Groote P (2005) Prognostic significance of circulating levels of angiogenic cytokines in patients with congestive heart failure. Am Heart J 150:137–143

    PubMed  CAS  Google Scholar 

  171. Ueno S, Ikeda U, Hojo Y, Arakawa H, Nonaka M, Yamamoto K, Shimada K (2001) Serum hepatocyte growth factor levels are increased in patients with congestive heart failure. J Card Fail 7:329–334

    PubMed  CAS  Google Scholar 

  172. Levin ER, Gardner DG, Samson WK (1998) Mechanisms of disease – natriuretic peptides. N Engl J Med 339:321–328

    PubMed  CAS  Google Scholar 

  173. Liu Y, Wilkinson FL, Kirton JP, Jeziorska M, Iizasa H, Sai Y, Nakashima E, Heagerty AM, Canfield AE, Alexander MY (2007) Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development. J Pathol 212:12–19

    PubMed  CAS  Google Scholar 

  174. Morishita R, Moriguchi A, Higaki J, Ogihara T (1999) Hepatocyte growth factor (HGF) as a potential index of severity of hypertension. Hypertens Res Clin Exp 22:161–167

    CAS  Google Scholar 

  175. Nakamura S, Morishita R, Moriguchi A, Yo Y, Nakamura Y, Hayashi S, Matsumoto K, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1998) Hepatocyte growth factor as a potential index of complication in diabetes mellitus. J Hypertens 16:2019–2026

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Christian Leo and Amedeo Chiribiri for their critical reading of the manuscript. This work was supported by funds from the Compagnia di San Paolo and the Association Francaise contre les Myopathies (AFM). V.S. is a Fellow of Università Italo Francese.

Author information

Authors and Affiliations

  1. Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Corso Massimo D’Azeglio 52, 10126, Turin, Italy

    V. Sala & T. Crepaldi

Authors
  1. V. Sala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Crepaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Crepaldi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sala, V., Crepaldi, T. Novel therapy for myocardial infarction: can HGF/Met be beneficial?. Cell. Mol. Life Sci. 68, 1703–1717 (2011). https://doi.org/10.1007/s00018-011-0633-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0633-6

Keywords

Search

Navigation