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OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway

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Abstract

Atherosclerotic plaques are characterized by hypoxic even anoxic areas and by high concentrations of oxidized lipoproteins. Moreover, unstable plaques attract a high number of macrophages despite the proapoptotic background within these plaques. Recently, it was shown that these macrophages are positive for Hif-1α. This subunit is a part of hypoxia-inducible factor 1 (Hif-1), a key transcriptional factor under hypoxia. Till date, it is not understood whether the Hif-system (consisting of Hif-1, Hif-2 and Hif-3) is involved in protection of macrophages under these proatherogenic conditions. The present study delineates that oxLDL causes fundamental changes in the regulation of the Hif-system in primary human macrophages. First, both oxLDL and hypoxia mediate accumulation of Hif-1α protein. Second, treatment with a combination of oxLDL and hypoxia is acting in an additive manner on Hif-1α protein content. Third, oxLDL alone does not increase Hif-2α protein, but abolishes the hypoxic induction of Hif-2α completely. OxLDL treatment alone was not toxic for macrophages under neither normoxia nor hypoxia. But, inhibition of Hif-pathway by adenoviral expression of a dominant-negative mutant combined with oxLDL treatment independently of the oxygen tension leads to apoptosis, as determined by caspase-3 activation and induction of DNA fragmentation. Furthermore, this inhibition also mediates the opening of the mitochondrial permeability transition pore. In conclusion, the present data show that Hif-1α regulation is essential for survival of oxLDL-treated macrophages independent of the oxygen tension. Therefore, this newly characterized mechanism might also have an important influence for the vulnerability of atherosclerotic plaques.

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References

  1. Bjornheden T, Levin M, Evaldsson M, Wiklund O (1999) Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler Thromb Vasc Biol 19:870–876

    Article  PubMed  CAS  Google Scholar 

  2. Blanc-Brude OP, Teissier E, Castier Y, Leseche G, Bijnens AP, Daemen M, Staels B, Mallat Z, Tedgui A (2007) IAP survivin regulates atherosclerotic macrophage survival. Arterioscler Thromb Vasc Biol 27:901–907

    Article  PubMed  CAS  Google Scholar 

  3. Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α. Blood 103:1124–1130. doi:10.1182/blood-2003-07-2427

    Article  PubMed  CAS  Google Scholar 

  4. Boullier A, Li Y, Quehenberger O, Palinski W, Tabas I, Witztum JL, Miller YI (2006) Minimally oxidized LDL offsets the apoptotic effects of extensively oxidized LDL and free cholesterol in macrophages. Arterioscler Thromb Vasc Biol 26:1169–1176. doi:10.1161/01.ATV.0000210279.97308.9a

    Article  PubMed  CAS  Google Scholar 

  5. Bracken CP, Whitelaw ML, Peet DJ (2003) The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 60:1376–1393. doi:10.1007/s00018-003-2370-y

    Article  PubMed  CAS  Google Scholar 

  6. Chen JH, Riazy M, Smith EM, Proud CG, Steinbrecher UP, Duronio V (2009) Oxidized LDL-mediated macrophage survival involves elongation factor-2 kinase. Arterioscler Thromb Vasc Biol 29:92–98. doi:10.1161/ATVBAHA.108.174599

    Article  PubMed  CAS  Google Scholar 

  7. de Nigris F, Gallo L, Sica V, Napoli C (2006) Glycoxidation of low-density lipoprotein promotes multiple apoptotic pathways and NFkB activation in human coronary cells. Basic Res Cardiol 101:101–108. doi:10.1007/s00395-005-0560-5

    Article  PubMed  Google Scholar 

  8. Dery MA, Michaud MD, Richard DE (2005) Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37:535–540. doi:10.1016/j.biocel.2004.08.012

    Article  PubMed  CAS  Google Scholar 

  9. Erbel C, Dengler TJ, Wangler S, Lasitschka F, Bea F, Wambsganss N, Hakimi M, Bockler D, Katus HA, Gleissner CA (2011) Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability. Basic Res Cardiol 106:125–134. doi:10.1007/s00395-010-0135-y

    Article  PubMed  CAS  Google Scholar 

  10. Ermak N, Lacour B, Drueke TB, Vicca S (2008) Role of reactive oxygen species and Bax in oxidized low density lipoprotein-induced apoptosis of human monocytes. Atherosclerosis 200:247–256. doi:10.1016/j.atherosclerosis.2007.12.052

    Article  PubMed  CAS  Google Scholar 

  11. Frede S, Stockmann C, Freitag P, Fandrey J (2006) Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kB. Biochem J 396:517–527. doi:10.1042/BJ20051839

    Article  PubMed  CAS  Google Scholar 

  12. Fulda S, Debatin KM (2007) HIF-1-regulated glucose metabolism: a key to apoptosis resistance? Cell Cycle 6:790–792. doi:10.4161/cc.6.7.4084

    Article  PubMed  CAS  Google Scholar 

  13. Garedew A, Henderson SO, Moncada S (2010) Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Differ 17:1540–1550. doi:10.1038/cdd.2010.27

    Article  PubMed  CAS  Google Scholar 

  14. Garedew A, Moncada S (2008) Mitochondrial dysfunction and HIF1α stabilization in inflammation. J Cell Sci 121:3468–3475. doi:10.1242/jcs.034660

    Article  PubMed  CAS  Google Scholar 

  15. Ginouves A, Ilc K, Macias N, Pouyssegur J, Berra E (2008) PHDs overactivation during chronic hypoxia “desensitizes” HIFalpha and protects cells from necrosis. Proc Natl Acad Sci USA 105:4745–4750

    Article  PubMed  CAS  Google Scholar 

  16. Gössl M, Herrmann J, Tang H, Versari D, Galili O, Mannheim D, Rajkumar SV, Lerman LO, Lerman A (2009) Prevention of vasa vasorum neovascularization attenuates early neointima formation in experimental hypercholesterolemia. Basic Res Cardiol 104:695–706. doi:10.1007/s00395-009-0036-0

    Article  PubMed  Google Scholar 

  17. Jiang G, Li T, Qiu Y, Rui Y, Chen W, Lou Y (2007) RNA interference for HIF-1alpha inhibits foam cells formation in vitro. Eur J Pharmacol 562:183–190. doi:10.1016/j.ejphar.2007.01.066

    Article  PubMed  CAS  Google Scholar 

  18. Kim HY, Kim YH, Nam BH, Kong HJ, Kim HH, Kim YJ, An WG, Cheong J (2007) HIF-1α expression in response to lipopolysaccaride mediates induction of hepatic inflammatory cytokine TNFa. Exp Cell Res 313:1866–1876. doi:10.1016/j.yexcr.2007.03.009

    Article  PubMed  CAS  Google Scholar 

  19. Kohlstedt K, Trouvain C, Namgaladze D, Fleming I (2011) Adipocyte-derived lipids increase angiotensin-converting enzyme (ACE) expression and modulate macrophage phenotype. Basic Res Cardiol 106:205–215. doi:10.1007/s00395-010-0137-9

    Article  PubMed  CAS  Google Scholar 

  20. Lall H, Coughlan K, Sumbayev VV (2008) HIF-1a protein is an essential factor for protection of myeloid cells against LPS-induced depletion of ATP and apoptosis that supports Toll-like receptor 4-mediated production of IL-6. Mol Immunol 45:3045–3049. doi:10.1016/j.molimm.2008.03.014

    Article  PubMed  CAS  Google Scholar 

  21. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004. doi:10.1128/MCB.21.12.3995-4004.2001

    Article  PubMed  CAS  Google Scholar 

  22. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874. doi:10.1038/nature01323

    Article  PubMed  CAS  Google Scholar 

  23. Maemura K, Hsieh CM, Jain MK, Fukumoto S, Layne MD, Liu Y, Kourembanas S, Yet SF, Perrella MA, Lee ME (1999) Generation of a dominant-negative mutant of endothelial PAS domain protein 1 by deletion of a potent C-terminal transactivation domain. J Biol Chem 274:31565–31570. doi:10.1074/jbc.274.44.31565

    Article  PubMed  CAS  Google Scholar 

  24. Mellor HR, Harris AL (2007) The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer. Cancer Metastasis Rev 26:553–566. doi:10.1007/s10555-007-9080-0

    Article  PubMed  CAS  Google Scholar 

  25. Nishi K, Oda T, Takabuchi S, Oda S, Fukuda K, Adachi T, Semenza GL, Shingu K, Hirota K (2008) LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner. Antioxid Redox Signal 10:983–995. doi:10.1089/ars.2007.1825

    Article  PubMed  CAS  Google Scholar 

  26. Page EL, Robitaille GA, Pouyssegur J, Richard DE (2002) Induction of hypoxia-inducible factor-1α by transcriptional and translational mechanisms. J Biol Chem 277:48403–48409. doi:10.1074/jbc.M209114200

    Article  PubMed  CAS  Google Scholar 

  27. Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, Di LF (1999) Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J 76:725–734

    Article  PubMed  CAS  Google Scholar 

  28. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J Immunol 178:7516–7519

    PubMed  CAS  Google Scholar 

  29. Riazy M, Chen JH, Steinbrecher UP (2009) VEGF secretion by macrophages is stimulated by lipid and protein components of OxLDL via PI3-kinase and PKCς activation and is independent of OxLDL uptake. Atherosclerosis 204:47–54. doi:10.1016/j.atherosclerosis.2008.08.004

    Article  PubMed  CAS  Google Scholar 

  30. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  PubMed  CAS  Google Scholar 

  31. Rossig L, Dimmeler S, Zeiher AM (2001) Apoptosis in the vascular wall and atherosclerosis. Basic Res Cardiol 96:11–22. doi:10.1007/s003950170073

    Article  PubMed  CAS  Google Scholar 

  32. Sanson M, Ingueneau C, Vindis C, Thiers JC, Glock Y, Rousseau H, Sawa Y, Bando Y, Mallat Z, Salvayre R, Negre-Salvayre A (2008) Oxygen-regulated protein-150 prevents calcium homeostasis deregulation and apoptosis induced by oxidized LDL in vascular cells. Cell Death Differ 15:1255–1265. doi:10.1038/cdd.2008.36

    Article  PubMed  CAS  Google Scholar 

  33. Shatrov VA, Sumbayev VV, Zhou J, Brune B (2003) Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1α (HIF-1α) accumulation via redox-dependent mechanisms. Blood 101:4847–4849. doi:10.1182/blood-2002-09-2711

    Article  PubMed  CAS  Google Scholar 

  34. Sluimer JC, Gasc JM, van Wanroij JL, Kisters N, Groeneweg M, Sollewijn Gelpke MD, Cleutjens JP, van den Akker LH, Corvol P, Wouters BG, Daemen MJ, Bijnens AP (2008) Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. JACC 51:1258–1265. doi:10.1016/j.jacc.2007.12.025

    PubMed  CAS  Google Scholar 

  35. Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS (2010) Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev 24:491–501. doi:10.1101/gad.1881410

    Article  PubMed  CAS  Google Scholar 

  36. Tsukamoto Y, Kuwabara K, Hirota S, Ikeda J, Stern D, Yanagi H, Matsumoto M, Ogawa S, Kitamura Y (1996) 150-kD oxygen-regulated protein is expressed in human atherosclerotic plaques and allows mononuclear phagocytes to withstand cellular stress on exposure to hypoxia and modified low density lipoprotein. J Clin Invest 98:1930–1941. doi:10.1172/JCI118994

    Article  PubMed  CAS  Google Scholar 

  37. Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, Clerici C (2004) Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1α and HIF-2α expression in lung epithelial cells: implication of natural antisense HIF-1α. J Biol Chem 279:14871–14878. doi:10.1074/jbc.M400461200

    Article  PubMed  CAS  Google Scholar 

  38. Vink A, Schoneveld AH, Lamers D, Houben AJS, van der Groep P, van Diest PJ, Pasterkamp G (2007) HIF-1a expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages. Atherosclerosis 195:e69–e75. doi:10.1016/j.atherosclerosis.2007.05.026

    Article  PubMed  CAS  Google Scholar 

  39. Willert M, Augstein A, Poitz DM, Schmeisser A, Strasser RH, Braun-Dullaeus RC (2010) Transcriptional regulation of Pim-1 kinase in vascular smooth muscle cells and its role for proliferation. Basic Res Cardiol 105:267–277. doi:10.1007/s00395-009-0055-x

    Article  PubMed  CAS  Google Scholar 

  40. Zhang C (2008) The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 103:398–406. doi:10.1007/s00395-008-0733-0

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

R.B.-D. was supported by grants of the SFB 655. This project was also supported by grants of the MedDrive program and the CRTD. Anita Männel and Peggy Barthel are acknowledged for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine and Cardiology, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    David M. Poitz, Antje Augstein, Sönke Weinert, Rüdiger C. Braun-Dullaeus, Ruth H. Strasser & Alexander Schmeisser

  2. Internal Medicine, Department of Cardiology, Angiology and Pneumology, Magdeburg University, Leipziger Str. 44, 39120, Magdeburg, Germany

    Sönke Weinert, Rüdiger C. Braun-Dullaeus & Alexander Schmeisser

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  1. David M. Poitz
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Correspondence to David M. Poitz.

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Poitz, D.M., Augstein, A., Weinert, S. et al. OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway. Basic Res Cardiol 106, 761–772 (2011). https://doi.org/10.1007/s00395-011-0186-8

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  • DOI: https://doi.org/10.1007/s00395-011-0186-8

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