Skip to main content
SpringerLink
Log in

Hypoxia-induced compensatory effect as related to Shh and HIF-1α in ischemia embryo rat heart

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Chronic cardiac ischemia/hypoxia induces coronary collateral formation and cardiomyocyte proliferation. Hypoxia can induce cellular adaptive responses, such as synthesis of VEGF for angiogenesis and IGF-2 for proliferation. Both reduce apoptotic effects to minimize injury or damage. To investigate the mechanism of neoangiogenesis and proliferation of fetal heart under umbilical cord compression situation, we used H9c2 cardiomyoblast cell culture, and in vivo embryonic hearts as our study models. Results showed hypoxia induced not only the increase of IGF-2 and VEGF expression but also the activation of their upstream regulatory genes, HIF-1α and Shh. The relationship between HIF-1α and Shh was further studied by using cyclopamine and 2-ME2, inhibitor of Shh and HIF-1α signaling, respectively, in the cardiomyoblast cell culture under hypoxia. We found that the two inhibitors not only blocked their own signal pathway, but also inhibited each other. The observations revealed when fetal heart under hypoxia that HIF-1α and Shh pathways maybe involve in cell proliferation and neoangiogenesis to minimize injury or damage, whereas the complex cross-talk between the two pathways remains unknown.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Chi NC, Karliner JS (2004) Molecular determinants of responses to myocardial ischemia/reperfusion injury: focus on hypoxia-inducible and heat shock factors. Cardiovasc Res 61:437–447

    Article  PubMed  CAS  Google Scholar 

  2. Clark KE, Irion GL (1992) Fetal hemodynamic response to maternal intravenous nicotine administration. Am J Obstet Gynecol 167:1624–1631

    PubMed  CAS  Google Scholar 

  3. Lyon HM, Holmes LB, Huang T (2003) Multiple congenital anomalies associated with in utero exposure of phenytoin: possible hypoxic ischemic mechanism? Birth Defects Res A Clin Mol Teratol 67:993–996

    Article  PubMed  CAS  Google Scholar 

  4. Carmeliet P, Dor Y, Herbert JM et al (1998) Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

    Article  PubMed  CAS  Google Scholar 

  5. Feldser D, Agani F, Iyer NV et al (1999) Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res 59:3915–3918

    PubMed  CAS  Google Scholar 

  6. Iyer NV, Kotch LE, Agani F et al (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12:149–162

    Article  PubMed  CAS  Google Scholar 

  7. Zhong H, Agani F, Baccala AA et al (1998) Increased expression of hypoxia-inducible factor 1α in rat and human prostate cancer. Cancer Res 58:5280–5284

    PubMed  CAS  Google Scholar 

  8. Stiehl DP, Jelkmann W, Wenger RH et al (2002) Normoxic induction of the hypoxia-inducible factor 1α by insulin and interleukin-1 beta involves the phosphatidylinositol 3-kinase pathway. FEBS Lett 512:157–162

    Article  PubMed  CAS  Google Scholar 

  9. Zelzer E, Levy Y, Kahana C et al (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J 17:5085–5094

    Article  PubMed  CAS  Google Scholar 

  10. Zhong H, Chiles K, Feldser D et al (2000) Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545

    PubMed  CAS  Google Scholar 

  11. Jetten AM (1991) Growth and differentiation factors in tracheobronchial epithelium. Am J Physiol 260:L361–L373

    PubMed  CAS  Google Scholar 

  12. D’Ercole AJ (1987) Somatomedin/insulin-like growth factors and fetal growth. J Dev Physiol 9:481–495

    PubMed  CAS  Google Scholar 

  13. Kobayashi S, Clemmons DR, Venkatachalam MA (1991) Colocalization of insulin-like growth factor binding protein with insulin-like growth factor-I. Am J Physiol 261:F22–F28

    PubMed  CAS  Google Scholar 

  14. Grothey A, Voigt W, Schober C et al (1999) The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors. J Cancer Res Clin Oncol 125:166–173

    Article  PubMed  CAS  Google Scholar 

  15. Rappolee DA, Strum KS, Behrendsten O et al (1992) Insulin-like growth factor II acts through an endogenous growth pathway regulated by imprinting in early mouse embryos. Genes Dev 6:939–952

    Article  PubMed  CAS  Google Scholar 

  16. Grant MB, Mames RN, Fitzgerald C et al (1993) Insulin-like growth factor as an angiogenic agent: in vivo and in vitro studies. Ann NY Acad Sci 692:230–242

    Article  PubMed  CAS  Google Scholar 

  17. Pola R, Ling LE, Aprahamian TR et al (2003) Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia. Circulation 108:479–485

    Article  PubMed  Google Scholar 

  18. Pola R, Ling LE, Silver M et al (2001) The morphogen sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factor. Nat Med 7:706–711

    Article  PubMed  CAS  Google Scholar 

  19. Magal E, Goldin E, Harel S et al (1988) Acute uteroplacental ischemic embryo: lactic acid accumulation and prostaglandin production in the fetal rat brain. J Neurochem 51:75–80

    Article  PubMed  CAS  Google Scholar 

  20. Levy R, Glozman S, Milman D et al (2002) Ischemic reperfusion brain injury in fetal transgenic mice with elevated levels of copper-zinc superoxide dismutase. J Perinat Med 30:158–165

    Article  PubMed  CAS  Google Scholar 

  21. Nishimaki H, Kasai K, Kozaki KI et al (2004) A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun 314:313–320

    Article  PubMed  CAS  Google Scholar 

  22. Giordano FJ, Gerber HP, Williams, SP et al (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  PubMed  CAS  Google Scholar 

  23. Byrne AT, Southgate J, Brison DR et al (2002) Regulation of apoptosis in the bovine blastocyst by insulin and the insulin-like growth factor (IGF) superfamily. Mol Reprod Dev 62:489–495

    Article  PubMed  CAS  Google Scholar 

  24. Steinbrech DS, Mehrara BJ, Saadeh PB et al (2000) Hypoxia increases insulin-like growth factor gene expression in rat osteoblasts. Ann Plast Surg 44:529–535

    Article  PubMed  CAS  Google Scholar 

  25. Averbukh E, Weiss O, Halpert M et al (1998) Gene expression of insulin-like growth factor-1, its receptor and binding proteins in retina under hypoxic conditions. Metabolism 47:1331–1336

    Article  PubMed  CAS  Google Scholar 

  26. Guan J, Skinner SJ, Beilharz EJ et al (1996) The movement of IGF-1 into the brain parenchyma after hypoxic-ischemic injury. Neuroreport 7:632–636

    Article  PubMed  CAS  Google Scholar 

  27. Giordano FJ, Ping P, McKirnan MD et al (1996) Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 2:534–539

    Article  PubMed  CAS  Google Scholar 

  28. Hendel RC, Henry TD, Rocha-Singh K et al (2000) Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation 101:118–121

    PubMed  CAS  Google Scholar 

  29. Laham RJ, Sellke FW, Edelman ER et al (1999) Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 100:1865–1871

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grant from the National Science Council of Republic of China (NSC94-2316-B-039-002).

Author information

Authors and Affiliations

  1. School of Applied Chemistry, Chung-Shan Medical University, Taichung, Taiwan

    Jin-Ming Hwang

  2. Department of Veterinary Medicine, National Chung-Hsing University, Taichung, 402, Taiwan

    Yi-Jiun Weng

  3. Graduate Institute of Basic Medical Science, China Medical University, Taichung, 404, Taiwan

    James A. Lin & Chih-Yang Huang

  4. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, 404, Taiwan

    Da-Tian Bau, Fu-Yang Ko, Fuu-Jen Tsai & Chih-Yang Huang

  5. Department of Pediatrics, Medical Research and Medical Genetics, China Medical College Hospital, Taichung, Taiwan

    Fuu-Jen Tsai

  6. Department of Healthcare Administration, Asia University, Taichung, Taiwan

    Chang-Hai Tsai

  7. Department of Biological Science and Technology, School of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan

    Chieh-Hsi Wu & Wei-Wen Kuo

  8. School of Medical Laboratory and Biotechnology, Chung-Shan Medical University, Taichung, 402, Taiwan

    Pei-Cheng Lin

  9. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

Authors
  1. Jin-Ming Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Jiun Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James A. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Da-Tian Bau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fu-Yang Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fuu-Jen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chang-Hai Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chieh-Hsi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pei-Cheng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chih-Yang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei-Wen Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Wen Kuo.

Additional information

Pei-Cheng Lin, Chih-Yang Huang, and Wei-Wen Kuo contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hwang, JM., Weng, YJ., Lin, J.A. et al. Hypoxia-induced compensatory effect as related to Shh and HIF-1α in ischemia embryo rat heart. Mol Cell Biochem 311, 179–187 (2008). https://doi.org/10.1007/s11010-008-9708-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-9708-6

Keywords

Search

Navigation