BACKGROUND: Diabetic cardiomyopathy is associated with a number of functional and structural pathological changes such as left ventricular dysfunction, cardiac remodeling, and apoptosis. The primary cause of diabetic cardiomyopathy is hyperglycemia, the metabolic hallmark of diabetes. Recent studies have shown that a diabetic environment suppresses hypoxia-inducible factor (HIF)-1α protein stability and function. The aim of this study was to analyze the functional role of HIF-1α in the development of diabetic cardiomyopathy. We have hypothesized that the partial deficiency of HIF-1α may compromise cardiac responses under diabetic conditions and increase susceptibility to diabetic cardiomyopathy. METHODS: Diabetes was induced by streptozotocin in wild type (Wt) and heterozygous Hif1a knock-out (Hif1a+/-) mice. Echocardiographic evaluations of left ventricular functional parameters, expression analyses by qPCR and Western blot, and cardiac histopathology assessments were performed in age-matched groups, diabetic, and non-diabetic Wt and Hif1a+/- mice. RESULTS: Five weeks after diabetes was established, a significant decrease in left ventricle fractional shortening was detected in diabetic Hif1a+/- but not in diabetic Wt mice. The combination effects of the partial deficiency of Hif1a and diabetes affected the gene expression profile of the heart, including reduced vascular endothelial growth factor A (Vegfa) expression. Adverse cardiac remodeling in the diabetic Hif1a+/- heart was shown by molecular changes in the expression of structural molecules and components of the extracellular matrix. CONCLUSIONS: We have shown a correlation between heterozygosity for Hif1α and adverse functional, molecular, and cellular changes associated with diabetic cardiomyopathy. Our results provide evidence that HIF-1α regulates early cardiac responses to diabetes, and that HIF-1α deregulation may influence the increased risk for diabetic cardiomyopathy.

Institute of Biotechnology AS CR Prague Czechia

Zobrazit více v PubMed

Boudina S, Abel ED. Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord. 2010;11(1):31–39. PubMed PMC

Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–241. PubMed PMC

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–1625. PubMed

Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–820. PubMed

Semenza GL. Oxygen sensing, homeostasis, and disease. New Engl J Med. 2011;365(6):537–547. PubMed

Bardos JI, Ashcroft M. Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta. 2005;1755(2):107–120. PubMed

Haddad JJ, Harb HL. Cytokines and the regulation of hypoxia-inducible factor (HIF)-1alpha. Int Immunopharmacol. 2005;5(3):461–483. PubMed

Klimova T, Chandel NS. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 2008;15(4):660–666. PubMed

Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000;275(33):25130–25138. PubMed

Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY. et al.Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149–162. PubMed PMC

Li J, Bosch-Marce M, Nanayakkara A, Savransky V, Fried SK, Semenza GL, Polotsky VY. Altered metabolic responses to intermitternt hypoxia in mice with partial deficiency of hypoxia-inducible factor 1 α. Physiol Genom. 2006;25(3):450–457. PubMed

Kline DD, Peng YJ, Manalo DJ, Semenza GL, Prabhakar NR. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci USA. 2002;99(2):821–826. PubMed PMC

Cai Z, Zhong H, Bosch-Marce M, Fox-Talbot K, Wang L, Wei C, Trush MA, Semenza GL. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovasc Res. 2008;77(3):463–470. PubMed

Huang Y, Hickey RP, Yeh JL, Liu D, Dadak A, Young LH, Johnson RS, Giordano FJ. Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. Faseb J. 2004;18(10):1138–1140. PubMed

Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K. et al.Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci USA. 2008;105(49):19426–19431. PubMed PMC

Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, Nastai M, Semenza GL, Harmon JW. 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. 2008;217(2):319–327. PubMed PMC

Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes. 2004;53(12):3226–3232. PubMed

Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, Galiano RD, Du XL, Grogan R, Galvez MG. et al.The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci USA. 2009;106(32):13505–13510. PubMed PMC

Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP. et al.Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation. 2002;105(3):373–379. PubMed

Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, Kirchmair R, Bahlman F, Walter D, Curry C. et al.Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation. 2005;111(16):2073–2085. PubMed

Mizushige K, Yao L, Noma T, Kiyomoto H, Yu Y, Hosomi N, Ohmori K, Matsuo H. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation. 2000;101(8):899–907. PubMed

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

Peng YJ, Yuan G, Ramakrishnan D, Sharma SD, Bosch-Marce M, Kumar GK, Semenza GL, Prabhakar NR. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 2006;577(Pt 2):705–716. PubMed PMC

Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, Zhang H, Strazza M, Rey S, Savino L. et al.Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res. 2007;101(12):1310–1318. PubMed

Bohuslavova R, Kolar F, Kuthanova L, Neckar J, Tichopad A, Pavlinkova G. Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia. J Appl Physiol. 2010;109(4):1195–1202. PubMed

Pavlinkova G, Salbaum JM, Kappen C. Maternal diabetes alters transcriptional programs in the developing embryo. BMC Genom. 2009;10:274. PubMed PMC

Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. PubMed PMC

Bohuslavova R, Skvorova L, Sedmera D, Semenza GL, Pavlinkova G. Increased susceptibility of HIF-1alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes. J Mol Cell Cardiol. 2013;60:129–141. PubMed

Sato T, Haimovici R, Kao R, Li AF, Roy S. Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells. Diabetes. 2002;51(5):1565–1571. PubMed

Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115(25):3213–3223. PubMed

Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006;98(5):596–605. PubMed

Yu X, Tesiram YA, Towner RA, Abbott A, Patterson E, Huang S, Garrett MW, Chandrasekaran S, Matsuzaki S, Szweda LI. et al.Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI) Cardiovasc Diabetol. 2007;6:6. PubMed PMC

Chang KC, Lo HM, Tseng YZ. Systolic elastance and resistance in the regulation of cardiac pumping function in early streptozotocin-diabetic rats. Exp Biol Med. 2002;227(4):251–259. PubMed

Hoit BD, Castro C, Bultron G, Knight S, Matlib MA. Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats. J Card Fail. 1999;5(4):324–333. PubMed

Caruso L, Yuen S, Smith J, Husain M, Opavsky MA. Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling. J Mol Cell Cardiol. 2010;48(6):1194–1205. PubMed

Zuliani G, Galvani M, Maggio M, Volpato S, Bandinelli S, Corsi AM, Lauretani F, Cherubini A, Guralnik JM, Fellin R. et al.Plasma soluble gp130 levels are increased in older subjects with metabolic syndrome. The role of insulin resistance. Atherosclerosis. 2010;213(1):319–324. PubMed PMC

Zymek P, Bujak M, Chatila K, Cieslak A, Thakker G, Entman ML, Frangogiannis NG. The role of platelet-derived growth factor signaling in healing myocardial infarcts. J Am Coll Cardiol. 2006;48(11):2315–2323. PubMed

Sokolovska J, Isajevs S, Sugoka O, Sharipova J, Lauberte L, Svirina D, Rostoka E, Sjakste T, Kalvinsh I, Sjakste N. Correction of glycaemia and GLUT1 level by mildronate in rat streptozotocin diabetes mellitus model. Cell Biochem Funct. 2011;29(1):55–63. PubMed

Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem. 2001;276(16):12645–12653. PubMed

Linnemann AK, O'Geen H, Keles S, Farnham PJ, Bresnick EH. Genetic framework for GATA factor function in vascular biology. Proc Natl Acad Sci USA. 2011;108(33):13641–13646. PubMed PMC

de Nooijer R, Bot I, von der Thusen JH, Leeuwenburgh MA, Overkleeft HS, Kraaijeveld AO, Dorland R, van Santbrink PJ, van Heiningen SH, Westra MM. et al.Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29(2):188–194. PubMed

Eltzschig HK, Carmeliet P. Hypoxia and inflammation. New Engl J Med. 2011;364(7):656–665. PubMed PMC

Wu L, Derynck R. Essential role of TGF-beta signaling in glucose-induced cell hypertrophy. Dev Cell. 2009;17(1):35–48. PubMed PMC

Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C. Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem. 2001;276(42):38527–38535. PubMed

Wei H, Bedja D, Koitabashi N, Xing D, Chen J, Fox-Talbot K, Rouf R, Chen S, Steenbergen C, Harmon JW. et al.Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-beta signaling. Proc Natl Acad Sci USA. 2012;109(14):E841–E850. PubMed PMC

Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002;51(6):1938–1948. PubMed

Marfella R, D'Amico M, Di Filippo C, Piegari E, Nappo F, Esposito K, Berrino L, Rossi F, Giugliano D. Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1. Diabetologia. 2002;45(8):1172–1181. PubMed

Pereira ER, Liao N, Neale GA, Hendershot LM. Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response. PloS one. 2010;5(9) doi:10.1371/journal.pone.0012521. PubMed PMC

Holscher M, Schafer K, Krull S, Farhat K, Hesse A, Silter M, Lin Y, Pichler BJ, Thistlethwaite P, El-Armouche A. et al.Unfavourable consequences of chronic cardiac HIF-1alpha stabilization. Cardiovasc Res. 2012;94(1):77–86. PubMed

Yamada N, Horikawa Y, Oda N, Iizuka K, Shihara N, Kishi S, Takeda J. Genetic variation in the hypoxia-inducible factor-1alpha gene is associated with type 2 diabetes in Japanese. J Clin Endocrinol Metab. 2005;90(10):5841–5847. PubMed

Hlatky MA, Quertermous T, Boothroyd DB, Priest JR, Glassford AJ, Myers RM, Fortmann SP, Iribarren C, Tabor HK, Assimes TL. et al.Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease. Am Heart J. 2007;154(6):1035–1042. PubMed

Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

Renal injury is accelerated by global hypoxia-inducible factor 1 alpha deficiency in a mouse model of STZ-induced diabetes