Skip to main content
SpringerLink
Log in

Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The mechanisms that contribute to the development of diabetes complications remain unclear. A defective reaction of tissues to hypoxia has recently emerged as a new pathogenic mechanism and consists of a complex repression of hypoxia-inducible factor (HIF), which is the main regulator of the adaptive response to hypoxia. This paper discusses the mechanisms by which hyperglycaemia contributes to HIF repression in diabetes. Furthermore, a comprehensive analysis of the functional relevance of these new findings to the development of chronic diabetes complications is provided, along with examples from animal models and clinics.

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

Similar content being viewed by others

References

  1. Arden GB, Sivaprasad S (2012) The pathogenesis of early retinal changes of diabetic retinopathy. Documenta ophthalmologica Adv in ophthalmol 124:15–26

    Article  CAS  Google Scholar 

  2. Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K et al (2008) Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A 105:19426–19431

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Edlund J, Hansell P, Fasching A, Liss P, Weis J, Glickson JD, Palm F (2009) Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging. Adv Exp Med Biol 645:199–204

    Article  PubMed  Google Scholar 

  4. Lee S, Morgan GA, Harris NR (2008) Ozagrel reverses streptozotocin-induced constriction of arterioles in rat retina. Microvasc Res 76:217–223

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Schaper NC, Huijberts M, Pickwell K (2008) Neurovascular control and neurogenic inflammation in diabetes. Diabetes Metab Res Rev 24(Suppl 1):S40–44

    Article  PubMed  Google Scholar 

  6. Flyvbjerg A (2010) Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol 6:94–101

    Article  PubMed  CAS  Google Scholar 

  7. Friederich M, Fasching A, Hansell P, Nordquist L, Palm F (2008) Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta 1777:935–940

    Article  PubMed  CAS  Google Scholar 

  8. Semenza GL (2010) Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2:336–361

    Article  PubMed  CAS  Google Scholar 

  9. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94:4273–4278

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22

    CAS  Google Scholar 

  11. Le Moan N, Houslay DM, Christian F, Houslay MD, Akassoglou K (2011) Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1alpha. Mol Cell 44:476–490

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA (2009) Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324:1289–1293

    Article  PubMed  CAS  Google Scholar 

  13. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T et al (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–293

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB et al (2011) SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell 19:416–428

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Nunez-O’Mara A, Berra E (2013) Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade. Biol Chem 394:459–469

    PubMed  Google Scholar 

  16. Devlin C, Greco S, Martelli F, Ivan M (2011) miR-210: more than a silent player in hypoxia. IUBMB Life 63:94–100

    PubMed  CAS  Google Scholar 

  17. Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS, Kung AL (2009) Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A 106:4260–4265

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Gabbay KH, Merola LO, Field RA (1966) Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 151:209–210

    Article  PubMed  CAS  Google Scholar 

  19. Greene DA, Sima AA, Stevens MJ, Feldman EL, Lattimer SA (1992) Complications: neuropathy, pathogenetic considerations. Diabetes Care 15:1902–1925

    Article  PubMed  CAS  Google Scholar 

  20. Tang WH, Wu S, Wong TM, Chung SK, Chung SS (2008) Polyol pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart. Free Radic Biol Med 45:602–610

    Article  PubMed  CAS  Google Scholar 

  21. Giardino I, Edelstein D, Brownlee M (1994) Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest 94:110–117

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Bento CF, Fernandes R, Ramalho J, Marques C, Shang F, Taylor A, Pereira P (2010) The chaperone-dependent ubiquitin ligase CHIP targets HIF-1alpha for degradation in the presence of methylglyoxal. PLoS ONE 5:e15062

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Ceradini DJ, Yao D, Grogan RH, Callaghan MJ, Edelstein D, Brownlee M, Gurtner GC (2008) Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J Biol Chem 283:10930–10938

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, Galiano RD, Du XL, Grogan R, Galvez MG et al (2009) The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A 106:13505–13510

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L (2004) Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes 53:3226–3232

    Article  PubMed  CAS  Google Scholar 

  26. Bento CF, Fernandes R, Matafome P, Sena C, Seica R, Pereira P (2010) Methylglyoxal-induced imbalance in the ratio VEGF/Ang-2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction. Exp Physiol 95:955–70

    PubMed  CAS  Google Scholar 

  27. Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E (2001) Regulation of vascular endothelial growth factor expression by advanced glycation end products. J Biol Chem 276:43836–43841

    Article  PubMed  CAS  Google Scholar 

  28. Pichiule P, Chavez JC, Schmidt AM, Vannucci SJ (2007) Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J Biol Chem 282:36330–36340

    Article  PubMed  CAS  Google Scholar 

  29. Wei K, Piecewicz SM, McGinnis LM, Taniguchi CM, Wiegand SJ, Anderson K, Chan CW, Mulligan KX, Kuo D, Yuan J et al (2013) A liver Hif-2alpha-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 19:1331–1337

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Rosenberger C, Khamaisi M, Abassi Z, Shilo V, Weksler-Zangen S, Goldfarb M, Shina A, Zibertrest F, Eckardt KU, Rosen S et al (2008) Adaptation to hypoxia in the diabetic rat kidney. Kidney Int 73:34–42

    Article  PubMed  CAS  Google Scholar 

  31. Wright WS, McElhatten RM, Messina JE, Harris NR (2010) Hypoxia and the expression of HIF-1alpha and HIF-2alpha in the retina of streptozotocin-injected mice and rats. Exp Eye Res 90:405–412

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416:15–18

    Article  PubMed  CAS  Google Scholar 

  33. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    Article  PubMed  CAS  Google Scholar 

  34. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185

    Article  PubMed  Google Scholar 

  35. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129:111–122

    Article  PubMed  CAS  Google Scholar 

  37. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10:273–284

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Chandel NS (2010) Mitochondrial regulation of oxygen sensing. Adv Exp Med Biol 661:339–354

    Article  PubMed  CAS  Google Scholar 

  39. Kaelin WG Jr (2005) ROS: really involved in oxygen sensing. Cell Metab 1:357–358

    Article  PubMed  CAS  Google Scholar 

  40. Kozhukhar AV, Yasinska IM, Sumbayev VV (2006) Nitric oxide inhibits HIF-1alpha protein accumulation under hypoxic conditions: implication of 2-oxoglutarate and iron. Biochimie 88:411–418

    Article  PubMed  CAS  Google Scholar 

  41. Pacher P, Szabo C (2005) Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme. Antioxid Redox Signal 7:1568–1580

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Martinez-Romero R, Canuelo A, Martinez-Lara E, Javier Oliver F, Cardenas S, Siles E (2009) Poly(ADP-ribose) polymerase-1 modulation of in vivo response of brain hypoxia-inducible factor-1 to hypoxia/reoxygenation is mediated by nitric oxide and factor inhibiting HIF. J Neurochem 111:150–159

    Article  PubMed  CAS  Google Scholar 

  43. Girgis CM, Cheng K, Scott CH, Gunton JE (2012) Novel links between HIFs, type 2 diabetes, and metabolic syndrome. Trends Endocrinol Metab 23:372–380

    Article  PubMed  CAS  Google Scholar 

  44. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ et al (2009) Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29:4467–4483

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Zhang X, Lam KS, Ye H, Chung SK, Zhou M, Wang Y, Xu A (2010) Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice. J Biol Chem 285:32869–32877

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Matsuura H, Ichiki T, Inoue E, Nomura M, Miyazaki R, Hashimoto T, Ikeda J, Takayanagi R, Fong GH, Sunagawa K (2013) Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance. Circulation 127:2078–2087

    Article  PubMed  CAS  Google Scholar 

  47. Jiang C, Qu A, Matsubara T, Chanturiya T, Jou W, Gavrilova O, Shah YM, Gonzalez FJ (2011) Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes 60:2484–2495

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, Mirtschink P, Ukropcova B, Gasperikova D, Pedrazzini T et al (2012) Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD + system. Genes Dev 26:259–270

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Ochiai D, Goda N, Hishiki T, Kanai M, Senoo-Matsuda N, Soga T, Johnson RS, Yoshimura Y, Suematsu M (2011) Disruption of HIF-1alpha in hepatocytes impairs glucose metabolism in diet-induced obesity mice. Biochem Biophys Res Commun 415:445–449

    Article  PubMed  CAS  Google Scholar 

  50. Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda Y, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M (2014) Loss of HIF-1alpha impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells. Am J Physiol Endocrinol Metab 306:E1065–E1076

    Article  PubMed  CAS  Google Scholar 

  51. Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Visk D, Haddad GG, Poellinger L, Peet DJ, Powell F et al (2010) The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 11:364–378

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Heinis M, Simon MT, Ilc K, Mazure NM, Pouyssegur J, Scharfmann R, Duvillie B (2010) Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha. Diabetes 59:662–669

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Cantley J, Selman C, Shukla D, Abramov AY, Forstreuter F, Esteban MA, Claret M, Lingard SJ, Clements M, Harten SK et al (2009) Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J Clin Invest 119:125–135

    PubMed  CAS  PubMed Central  Google Scholar 

  54. Zehetner J, Danzer C, Collins S, Eckhardt K, Gerber PA, Ballschmieter P, Galvanovskis J, Shimomura K, Ashcroft FM, Thorens B et al (2008) PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells. Genes Dev 22:3135–3146

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Puri S, Cano DA, Hebrok M (2009) A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes 58:433–441

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ et al (2005) Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122:337–349

    Article  PubMed  CAS  Google Scholar 

  57. Cheng K, Ho K, Stokes R, Scott C, Lau SM, Hawthorne WJ, O’Connell PJ, Loudovaris T, Kay TW, Kulkarni RN et al (2010) Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets. J Clin Invest

  58. Zheng X, Wang X, Ma Z, Gupta Sunkari V, Botusan I, Takeda T, Bjorklund A, Inoue M, Catrina SB, Brismar K et al (2012) Acute hypoxia induces apoptosis of pancreatic beta-cell by activation of the unfolded protein response and upregulation of CHOP. Cell Death Dis 3:e322

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Stokes RA, Cheng K, Deters N, Lau SM, Hawthorne WJ, O’Connell PJ, Stolp J, Grey S, Loudovaris T, Kay TW et al (2012) Hypoxia-inducible factor 1alpha (HIF-1alpha) potentiates beta-cell survival after islet transplantation of human and mouse islets. Cell Transplant

  60. Persson MF, Franzen S, Catrina SB, Dallner G, Hansell P, Brismar K, Palm F (2012) Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes. Diabetologia

  61. Izuhara Y, Nangaku M, Inagi R, Tominaga N, Aizawa T, Kurokawa K, Van Ypersele De Strihou C, Miyata T (2005) Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol 16:3631–3641

    Article  PubMed  CAS  Google Scholar 

  62. Gu HF, Zheng X, Abu Seman N, Gu T, Botusan IR, Sunkari VG, Lokman EF, Brismar K, Catrina SB (2012) Impact of the hypoxia-inducible factor-1 alpha (HIF-1alpha) Pro582Ser polymorphism on diabetes nephropathy. Diabetes care

  63. Isoe T, Makino Y, Mizumoto K, Sakagami H, Fujita Y, Honjo J, Takiyama Y, Itoh H, Haneda M (2010) High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int 78(1):48–59

    Article  PubMed  CAS  Google Scholar 

  64. Makino H, Miyamoto Y, Sawai K, Mori K, Mukoyama M, Nakao K, Yoshimasa Y, Suga S (2006) Altered gene expression related to glomerulogenesis and podocyte structure in early diabetic nephropathy of db/db mice and its restoration by pioglitazone. Diabetes 55:2747–2756

    Article  PubMed  CAS  Google Scholar 

  65. Xu X, Chen P, Zheng Q, Wang Y, Chen W (2011) Effect of pioglitazone on diabetic nephropathy and expression of HIF-1alpha and VEGF in the renal tissues of type 2 diabetic rats. Diabetes Res Clin Pract 60:981–92

    Google Scholar 

  66. Gautier-Stein A, Soty M, Chilloux J, Zitoun C, Rajas F, Mithieux G (2012) Glucotoxicity induces glucose-6-phosphatase catalytic unit expression by acting on the interaction of HIF-1alpha with CREB-binding protein. Diabetes 61:2451–2460

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Katavetin P, Miyata T, Inagi R, Tanaka T, Sassa R, Ingelfinger JR, Fujita T, Nangaku M (2006) High glucose blunts vascular endothelial growth factor response to hypoxia via the oxidative stress-regulated hypoxia-inducible factor/hypoxia-responsible element pathway. J Am Soc Nephrol 17:1405–1413

    Article  PubMed  CAS  Google Scholar 

  68. Ohtomo S, Nangaku M, Izuhara Y, Takizawa S, Strihou CY, Miyata T (2008) Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model. Nephrol Dial Transplant 23:1166–1172

    Article  PubMed  CAS  Google Scholar 

  69. Theilig F, Enke AK, Scolari B, Polzin D, Bachmann S, Koesters R (2011) Tubular deficiency of von Hippel-Lindau attenuates renal disease progression in anti-GBM glomerulonephritis. Am J Pathol 179:2177–88

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Kudo Y, Kakinuma Y, Mori Y, Morimoto N, Karashima T, Furihata M, Sato T, Shuin T, Sugiura T (2005) Hypoxia-inducible factor-1alpha is involved in the attenuation of experimentally induced rat glomerulonephritis. Nephron Exp Nephrol 100:e95–103

    Article  PubMed  CAS  Google Scholar 

  71. Flight MH (2013) Deal watch: astraZeneca bets on FibroGen’s anaemia drug. Nat Rev Drug Discov 12:730

    Article  PubMed  Google Scholar 

  72. Hashmi S, Al-Salam S (2012) HIF-1alpha in the heart: a double agent? Cardiol Rev 20:268–73

    Article  PubMed  Google Scholar 

  73. Malmberg K, Norhammar A, Wedel H, Ryden L (1999) Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the diabetes and insulin-glucose infusion in acute myocardial infarction (DIGAMI) study. Circulation 99:2626–2632

    Article  PubMed  CAS  Google Scholar 

  74. O’Sullivan JJ, Conroy RM, Robinson K, Hickey N, Mulcahy R (1991) In-hospital prognosis of patients with fasting hyperglycemia after first myocardial infarction. Diabetes Care 14:758–760

    Article  PubMed  Google Scholar 

  75. Marfella R, Esposito K, Nappo F, Siniscalchi M, Sasso FC, Portoghese M, Di Marino MP, Baldi A, Cuzzocrea S, Di Filippo C et al (2004) Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes 53:2383–2391

    Article  PubMed  CAS  Google Scholar 

  76. Mao X, Wang T, Liu Y, Irwin MG, Ou JS, Liao XL, Gao X, Xu Y, Ng KF, Vanhoutte PM et al (2013) N-acetylcysteine and allopurinol confer synergy in attenuating myocardial ischemia injury via restoring HIF-1alpha/HO-1 signaling in diabetic rats. PLoS ONE 8:e68949

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  77. Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E et al (2009) Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 9:512–524

    Article  PubMed  CAS  Google Scholar 

  78. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298:1180–1188

    Article  PubMed  CAS  Google Scholar 

  79. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471

    Article  PubMed  CAS  Google Scholar 

  80. Greco S, Fasanaro P, Castelvecchio S, D’Alessandra Y, Arcelli D, Di Donato M, Malavazos A, Capogrossi MC, Menicanti L, Martelli F (2012) MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes 61:1633–1641

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Xue W, Cai L, Tan Y, Thistlethwaite P, Kang YJ, Li X, Feng W (2010) Cardiac-specific overexpression of HIF-1{alpha} prevents deterioration of glycolytic pathway and cardiac remodeling in streptozotocin-induced diabetic mice. Am J Pathol 177:97–105

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler AA 3rd (2008) Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. J Cardiovasc Pharmacol 51:178–187

    Article  PubMed  CAS  Google Scholar 

  83. Amin AH, Abd Elmageed ZY, Nair D, Partyka MI, Kadowitz PJ, Belmadani S, Matrougui K (2010) Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. Lab Invest 90:985–96

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Kang LN, Chen Q, Wang L, Gao L, Meng K, Chen JH, Ferro A, Xu B (2009) Decreased mobilization of endothelial progenitor cells contributes to impaired neovascularization in diabetes. Clin Exp Pharmacol Physiol 36:E47–E56

    Article  PubMed  CAS  Google Scholar 

  85. Sarkar K, Fox-Talbot K, Steenbergen C, Bosch-Marce M, Semenza GL (2009) Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci U S A 106:18769–18774

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda J, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M (2010) Knockdown of hypoxia-inducible factor-1 alpha ameliorates insulin-stimulated glucose uptake in the skeletal muscle cellsEASD meeting, Stockholm, Sweden

  87. Mason S, Johnson RS (2007) The role of HIF-1 in hypoxic response in the skeletal muscle. Adv Exp Med Biol 618:229–244

    Article  PubMed  Google Scholar 

  88. Rasbach KA, Gupta RK, Ruas JL, Wu J, Naseri E, Estall JL, Spiegelman BM (2010) PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A 107:21866–21871

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. Elson DA, Ryan HE, Snow JW, Johnson R, Arbeit JM (2000) Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res 60:6189–6195

    PubMed  CAS  Google Scholar 

  90. Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, Nastai M, Semenza GL, Harmon JW (2008) Age-dependent impairment of HIF-1alpha expression in diabetic mice: correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol 217:319–327

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  91. Wetterau M, George F, Weinstein A, Nguyen PD, Tutela JP, Knobel D, Cohen Ba O, Warren SM, Saadeh PB (2011) Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound repair and regen : official publ of the Wound Healing Soc [and] the Eur Tissue Repair Soc 19:481–486

    Article  Google Scholar 

  92. Hou Z, Nie C, Si Z, Ma Y (2013) Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1alpha. Diabetes Res Clin Pract

  93. Bursell SE, Clermont AC, Kinsley BT, Simonson DC, Aiello LM, Wolpert HA (1996) Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy. Invest Ophthalmol Vis Sci 37:886–897

    PubMed  CAS  Google Scholar 

  94. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  PubMed  CAS  Google Scholar 

  95. Lim JI, Spee C, Hinton DR (2010) A comparison of hypoxia-inducible factor-alpha in surgically exised neovascular membranes of patients with diabetes compared with epiretinal membranes in nondiabetic patients. Retina

  96. Kondo T, Kahn CR (2004) Altered insulin signaling in retinal tissue in diabetic states. J Biol Chem 279:37997–38006

    Article  PubMed  CAS  Google Scholar 

  97. Garcia-Ramirez M, Hernandez C, Simo R (2008) Expression of erythropoietin and its receptor in the human retina: a comparative study of diabetic and nondiabetic subjects. Diabetes Care 31:1189–1194

    Article  PubMed  Google Scholar 

  98. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E (2002) Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277:27975–27981

    Article  PubMed  CAS  Google Scholar 

  99. Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2002) Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. JClinInvest 109:805–815

    CAS  Google Scholar 

  100. Yang P, Reece EA (2011) Role of HIF-1alpha in maternal hyperglycemia-induced embryonic vasculopathy. Am J Obstet Gynecol 204(332):e331–337

    Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Family Erling-Persson Foundation, the Swedish Research Council, the von Kantzow Foundation and the Stockholm County Council.

Conflict of interest

There are no other conflicts of interest for this study.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, L1:01, 17176, Stockholm, Sweden

    Sergiu-Bogdan Catrina

  2. Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden

    Sergiu-Bogdan Catrina

Authors
  1. Sergiu-Bogdan Catrina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergiu-Bogdan Catrina.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Catrina, SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med 92, 1025–1034 (2014). https://doi.org/10.1007/s00109-014-1166-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1166-x

Keywords

Search

Navigation