Skip to main content

Advertisement

SpringerLink
Log in

The hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

An Erratum to this article was published on 02 February 2007

Abstract

Objectives

The response to hypoxia is primarily mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) which leads to the induction of a variety of adaptive gene products including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). This study was designed to test the hypothesis that HIF-1 and its target genes would be upregulated in the ventricular myocardium of infants with cyanotic congenital cardiac defects.

Methods

14 infants with cyanotic (n = 7) or acyanotic cardiac defects (n = 7) were investigated. Samples from the right ventricular myocardium taken immediately after aortic clamping were studied for protein expression and DNA-binding activity.

Results

Protein levels of HIF-1α were significantly elevated in patients with cyanotic compared to acyanotic congenital heart disease and inversely correlated with the degree of hypoxemia. This response was accompanied by significantly enhanced HIF-1 DNA binding activity. Furthermore, protein levels of VEGF and eNOS were significantly higher in the myocardium of cyanotic than of acyanotic infants. To test the potential involvement of upstream regulatory pathways, activation of MAP kinases was determined. Intramyocardial levels of phosphorylated p38 MAP kinase, but not of ERK1/2 were significantly higher in infants with cyanotic compared to those with acyanotic congenital heart disease and inversely correlated to hypoxemia.

Conclusions

These findings show that chronic hypoxemia is associated with the induction and stabilization of the transcription factor HIF-1 as well as its target genes VEGF and eNOS in the myocardium of infants with cyanotic cardiac defects. Thus, stabilization of HIF-1 and induction of the adaptive hypoxia response could particularly participate in myocardial remodeling in children with congenital cardiac defects and chronic hypoxemia.

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

Similar content being viewed by others

References

  1. Andrews NC, Faller DV (1991) A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 19:2499

    Article  CAS  PubMed  Google Scholar 

  2. BelAiba RS, Djordjevic T, Bonello S, Flugel D, Hess J, Kietzmann T, Gorlach A (2004) Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells. Biol Chem 385:249–257

    Article  CAS  PubMed  Google Scholar 

  3. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH (1996) Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res 79:162–173

    CAS  PubMed  Google Scholar 

  4. Burton PB, Owen VJ, Hafizi S, Barton PJ, Carr-White G, Koh T, De Souza A, Yacoub MH, Pepper JR (2000) Vascular endothelial growth factor release following coronary artery bypass surgery: extracorporeal circulation versus ‘beating heart-surgery. Eur Heart J 21:1708–1713

    Article  CAS  PubMed  Google Scholar 

  5. Coulet F, Nadaud S, Agrapart M, Soubrier F (2003) Identification of hypoxia- response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 278:46230–46240

    Article  CAS  PubMed  Google Scholar 

  6. Couvelard A, O’Toole D, Leek R, Turley H, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F (2005) Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas. Histopathology 46:668–676

    Article  CAS  PubMed  Google Scholar 

  7. Felaco M, Grilli A, Gorbunov N, Di Napoli P, De Lutiis MA, Di Giulio C, Taccardi AA, Barsotti A, Barbacane RC, Reale M, Conti P (2000) Endothelial NOS expression and ischemia-reperfusion in isolated working rat heart from hypoxic and hyperoxic conditions. Biochim Biophys Acta 1524:203–211

    CAS  PubMed  Google Scholar 

  8. Feng Q, Song W, Lu X, Hamilton JA, Lei M, Peng T, Yee SP (2002) Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation 106:873–879

    Article  CAS  PubMed  Google Scholar 

  9. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611

    Article  CAS  PubMed  Google Scholar 

  10. Ferreiro CR, Chagas AC, Carvalho MH, Dantas AP, Jatene MB, Bento De Souza LC, Lemos Da Luz P (2001) Influence of hypoxia on nitric oxide synthase activity and gene expression in children with congenital heart disease: a novel pathophysiological adaptive mechanism. Circulation 103:2272–2276

    CAS  PubMed  Google Scholar 

  11. Forkel J, Chen X, Wandinger S, Keser F, Duschin A, Schwanke U, Frede S, Massoudy P, Schulz R, Jakob H, Heusch G (2004) Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia. Am J Physiol Heart Circ Physiol 286:545–551

    Article  Google Scholar 

  12. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factorinduced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98:2604–2609

    Article  CAS  PubMed  Google Scholar 

  13. Giordano FJ, Gerber HP, Williams SP, VanBruggen N, Bunting S, Ruiz-Lozano P, Gu Y, Nath AK, Huang Y, Hickey R, Dalton N, Peterson KL, Ross J, Jr., Chien KR, Ferrara N (2001) A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci USA 98:5780–5785

    Article  CAS  PubMed  Google Scholar 

  14. Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R (2001) Thrombin activates the hypoxiainducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res 89:47–54

    Article  CAS  PubMed  Google Scholar 

  15. Hellwig-Burgel T, Stiehl DP,Wagner AE, Metzen E, Jelkmann W (2005) Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res 25:297–310

    Article  PubMed  Google Scholar 

  16. Himeno W, Akagi T, Furui J, Maeno Y, Ishii M, Kosai K, Murohara T, Kato H (2003) Increased angiogenic growth factor in cyanotic congenital heart disease. Pediatr Cardiol 24:127–132

    Article  CAS  PubMed  Google Scholar 

  17. Hood JD, Meininger CJ, Ziche M, Granger HJ (1998) VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274:1054–1058

    Google Scholar 

  18. Hu J, Sun P, Ruan X, Chao A, Lin Y, Li XY (2005) Mechanism of myocardial microvessel formation in cyanotic congenital heart disease. Circ J 69:1089–1093

    Article  PubMed  Google Scholar 

  19. Jurgensen JS, Rosenberger C, Wiesener MS, Warnecke C, Horstrup JH, Grafe M, Philipp S, Griethe W, Maxwell PH, Frei U, Bachmann S, Willenbrock R, Eckardt KU (2004) Persistent induction of HIF- 1alpha and -2alpha in cardiomyocytes and stromal cells of ischemic myocardium. Faseb J 18:1415–1417

    PubMed  Google Scholar 

  20. Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, Thistlethwaite PA (2005) Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol 46:2116–1124

    Article  CAS  PubMed  Google Scholar 

  21. Kietzmann T, Gorlach A (2005) Reactive oxygen species in the control of hypoxia- inducible factor-mediated gene expression. Semin Cell Dev Biol 16:474–486

    Article  CAS  PubMed  Google Scholar 

  22. Kietzmann T, Jungermann K, Gorlach A (2003) Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases. Thromb Haemost 89:666–673

    CAS  PubMed  Google Scholar 

  23. Kim CH, Cho YS, Chun YS, Park JW, Kim MS (2002) Early expression of myocardial HIF-1alpha in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway. Circ Res 90:25–33

    Article  Google Scholar 

  24. Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA (2000) Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 342:626–633

    Article  CAS  PubMed  Google Scholar 

  25. Mazure NM, Brahimi-Horn MC, Pouyssegur J (2003) Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr Pharm Des 9:531–541

    Article  CAS  PubMed  Google Scholar 

  26. Namba T, Koike H, Murakami K, Aoki M, Makino H, Hashiya N, Ogihara T, Kaneda Y, Kohno M, Morishita R (2003) Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. Circulation 108:2250–2257

    Article  CAS  PubMed  Google Scholar 

  27. Parisi Q, Biondi-Zoccai GG, Abbate A, Santini D, Vasaturo F, Scarpa S, Bussani R, Leone AM, Petrolini A, Silvestri F, Biasucci LM, Baldi A (2005) Hypoxia inducible factor-1 expression mediates myocardial response to ischemia late after acute myocardial infarction. Int J Cardiol 99:337–339

    Article  PubMed  Google Scholar 

  28. Philipp S, Cui L, Ludolph B, Kelm M, Schulz R, Cohen MV, Downey JM (2006) Desferoxamine and ethyl-3,4-dihydroxybenzoate protect myocardium by activating NOS and generating mitochondrial ROS. Am J Physiol Heart Circ Physiol 290:450–457

    Article  Google Scholar 

  29. Qing M, Schumacher K, Heise R, Woltje M, Vazquez-Jimenez JF, Richter T, Arranda- Carrero M, Hess J, von Bernuth G, Seghaye MC (2003) Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects. J Am Coll Cardiol 41:2266–2274

    Article  CAS  PubMed  Google Scholar 

  30. Rapino C, Bianchi G, Di Giulio C, Centurione L, Cacchio M, Antonucci A, Cataldi A (2005) HIF-1alpha cytoplasmic accumulation is associated with cell death in old rat cerebral cortex exposed to intermittent hypoxia. Aging Cell 4:177–185

    Article  CAS  PubMed  Google Scholar 

  31. Semenza GL (2004) O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J Appl Physiol 96:1173–1177; discussion 117–1172

    Article  CAS  PubMed  Google Scholar 

  32. Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, Chang H (2002) Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 54:576–583

    Article  CAS  PubMed  Google Scholar 

  33. Starnes SL, Duncan BW, Kneebone JM, Rosenthal GL, Jones TK, Grifka RG, Cecchin F, Owens DJ, Fearneyhough C, Lupinetti FM (2000) Vascular endothelial growth factor and basic fibroblast growth factor in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 119:534–539

    Article  CAS  PubMed  Google Scholar 

  34. Tammela T, Enholm B, Alitalo K, Paavonen K (2005) The biology of vascular endothelial growth factors. Cardiovasc Res 65:550–563

    Article  CAS  PubMed  Google Scholar 

  35. Tomanek RJ, Zheng W, Yue X (2004) Growth factor activation in myocardial vascularization: therapeutic implications. Mol Cell Biochem 264:3–11

    Article  CAS  PubMed  Google Scholar 

  36. Zhao X, Lu X, Feng Q (2002) Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis. Am J Physiol Heart Circ Physiol 283:2371–2378

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Pediatric Cardiology, Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany

    M. Quing, K. Schumacher & M.-C. Seghaye MD

  2. Dept. of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich Technical University Munich, 80636, Munich, Germany

    A. Görlach & J. Hess

  3. Interdisciplinary Center for Clinical Research, BIOMAT Aachen University Hospital, Aachen, Germany

    M. Wöltje

  4. Dept. of Pediatric Cardiac Surgery, Aachen University Hospital, Aachen, Germany

    J. F. Vazquez-Jimenez

Authors
  1. M. Quing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Görlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Wöltje
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. F. Vazquez-Jimenez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M.-C. Seghaye MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A. Görlach or M.-C. Seghaye MD.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00395-007-0654-3.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quing, M., Görlach, A., Schumacher, K. et al. The hypoxia-inducible factor HIF-1 promotes intramyocardial expression of VEGF in infants with congenital cardiac defects. Basic Res Cardiol 102, 224–232 (2007). https://doi.org/10.1007/s00395-007-0639-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-007-0639-2

Key words

Search

Navigation