Oxygen, oxidative stress, hypoxia, and heart failure

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Address correspondence to: Frank J. Giordano, Department of Medicine, Yale University School of Medicine, BCMM 436C, 295 Congress Avenue, New Haven, Connecticut 06510, USA. Phone: (203) 785-7361; Fax: (203) 737-2290; E-mail: ude.elay@onadroiG.knarF.

Abstract

A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.

Abstract

The mammalian heart is an obligate aerobic organ. At a resting pulse rate, the heart consumes approximately 8–15 ml O₂/min/100 g tissue. This is significantly more than that consumed by the brain (approximately 3 ml O₂/min/100 g tissue) and can increase to more than 70 ml O₂/min/100 g myocardial tissue during vigorous exercise (1, 2). Mammalian heart muscle cannot produce enough energy under anaerobic conditions to maintain essential cellular processes; thus, a constant supply of oxygen is indispensable to sustain cardiac function and viability. The story of oxygen in the heart is complex, however, and goes well beyond its role in energy metabolism.

Oxygen is a major determinant of myocardial gene expression, and as myocardial O₂ levels decrease, either during isolated hypoxia or ischemia-associated hypoxia, gene expression patterns in the heart are significantly altered (3). Oxygen participates in the generation of NO, which plays a critical role in determining vascular tone, cardiac contractility, and a variety of additional parameters. Oxygen is also central in the generation of reactive oxygen species (ROS), which can participate as benevolent molecules in cell signaling processes or can induce irreversible cellular damage and death. Oxygen is thus both vital and deleterious (4).

Footnotes

Nonstandard abbreviations used: ARNT, aryl hydrocarbon nuclear translocase; ASK-1, apoptosis-signaling kinase 1; ATII, angiotensin II; HIF-1α, hypoxia-inducible factor 1α; MI, myocardial infarction; NOS, NO synthase; SOD, superoxide dismutase; VHL, von Hippel–Lindau protein; XO, xanthine oxidase.

Conflict of interest: The author has declared that no conflict of interest exists.

Footnotes

References

1. West, J.B. 1991. Cardiac energetics and myocardial oxygen consumption. Physiologic basis of medical practice. Williams and Wilkins. Baltimore, Maryland, USA. 250–260.
2. Braunwald, E. 2001. Coronary blood flow and myocardial ischemia. Heart disease: a textbook of cardiovascular medicine. W.B. Saunders Company. Philadelphia, Pennsylvania, USA. 1161–1183.
3. Huang Y, et al Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J.2004;18:1138–1140.[PubMed]
4. Davies KJOxidative stress: the paradox of aerobic life. Biochem. Soc. Symp.1995;61:1–31.[PubMed]
5. Jafri MS, Dudycha SJ, O’Rourke BCardiac energy metabolism: models of cellular respiration. Annu. Rev. Biomed. Eng.2001;3:57–81.[PubMed]
6. Ide T, et al Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res.1999;85:357–363.[PubMed]
7. Miwa S, Brand MDMitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem. Soc. Trans.2003;31:1300–1301.[PubMed]
8. Genova ML, et al Mitochondrial production of oxygen radical species and the role of Coenzyme Q as an antioxidant. Exp. Biol. Med. (Maywood).2003;228:506–513.[PubMed]
9. Toufektsian MC, Boucher FR, Tanguy S, Morel S, de Leiris JGCardiac toxicity of singlet oxygen: implication in reperfusion injury. Antioxid. Redox. Signal.2001;3:63–69.[PubMed]
10. Seshiah PN, et al Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ. Res.2002;91:406–413.[PubMed]
11. Xia Y, Tsai AL, Berka V, Zweier JL. Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J. Biol. Chem.1998;273:25804–25808.[PubMed]
12. Xia Y, Roman LJ, Masters BS, Zweier JLInducible nitric-oxide synthase generates superoxide from the reductase domain. J. Biol. Chem.1998;273:22635–22639.[PubMed]
13. Griendling KK, Sorescu D, Ushio-Fukai MNAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res.2000;86:494–501.[PubMed]
14. Sawyer DB, et al Role of oxidative stress in myocardial hypertrophy and failure. J. Mol. Cell. Cardiol.2002;34:379–388.[PubMed]
15. Thannickal VJ, Fanburg BLReactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell Mol. Physiol.2000;279:L1005–L1028.[PubMed]
16. Bendall JK, Cave AC, Heymes C, Gall N, Shah AMPivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation.2002;105:293–296.[PubMed]
17. Wu ML, Chan CC, Su MJPossible mechanism(s) of arachidonic acid-induced intracellular acidosis in rat cardiac myocytes. Circ. Res.2000;86:E55–E62.[PubMed]
18. Sauer H, et al Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells. Exp. Cell Res.2004;294:313–324.[PubMed]
19. Heymes C, et al Increased myocardial NADPH oxidase activity in human heart failure. J. Am. Coll. Cardiol.2003;41:2164–2171.[PubMed]
20. Sabri A, Hughie HH, Lucchesi PARegulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes. Antioxid. Redox Signal.2003;5:731–740.[PubMed]
21. Nordberg J, Arner ESReactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic. Biol. Med.2001;31:1287–1312.[PubMed]
22. Kirkman HN, Gaetani GFCatalase: a tetrameric enzyme with four tightly bound molecules of NADPH. Proc. Natl. Acad. Sci. U. S. A.1984;81:4343–4347.
23. Kirkman HN, Rolfo M, Ferraris AM, Gaetani GF. Mechanisms of protection of catalase by NADPH. Kinetics and stoichiometry. J. Biol. Chem.1999;274:13908–13914.[PubMed]
24. Ursini F, et al Diversity of glutathione peroxidases. Methods Enzymol.1995;252:38–53.[PubMed]
25. de Haan JB, et al Fibroblasts derived from Gpx1 knockout mice display senescent-like features and are susceptible to H2O2-mediated cell death. Free. Radic. Biol. Med.2004;36:53–64.[PubMed]
26. Conrad M, et al Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol. Cell. Biol.2004;24:9414–9423.
27. Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RAReactive oxygen species, cell signaling, and cell injury. Free Radic. Biol. Med.2000;28:1456–1462.[PubMed]
28. Nishida M, et al G alpha(i) and G alpha(o) are target proteins of reactive oxygen species. Nature.2000;408:492–495.[PubMed]
29. Griendling KK, FitzGerald GAOxidative stress and cardiovascular injury: part I: basic mechanisms and in vivo monitoring of ROS. Circulation.2003;108:1912–1916.[PubMed]
30. Machida Y, et al Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium. Am. J. Physiol. Heart Circ. Physiol.2003;284:H449–H455.[PubMed]
31. Hirotani S, et al Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation.2002;105:509–515.[PubMed]
32. Hsu TC, Young MR, Cmarik J, Colburn NHActivator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis. Free Radic. Biol. Med.2000;28:1338–1348.[PubMed]
33. Turpaev KTReactive oxygen species and regulation of gene expression. Biochemistry Mosc.2002;67:281–292.[PubMed]
34. Wu HM, Chi KH, Lin WWProteasome inhibitors stimulate activator protein-1 pathway via reactive oxygen species production. FEBS Lett.2002;526:101–105.[PubMed]
35. Hemnani T, Parihar MSReactive oxygen species and oxidative DNA damage. Indian J. Physiol. Pharmacol.1998;42:440–452.[PubMed]
36. Suematsu N, et al Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation.2003;107:1418–1423.[PubMed]
37. Rathore N, John S, Kale M, Bhatnagar DLipid peroxidation and antioxidant enzymes in isoproterenol induced oxidative stress in rat tissues. Pharmacol. Res.1998;38:297–303.[PubMed]
38. Thollon C, Iliou JP, Cambarrat C, Robin F, Vilaine JPNature of the cardiomyocyte injury induced by lipid hydroperoxides. Cardiovasc. Res.1995;30:648–655.[PubMed]
39. Rahman IOxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J. Biochem. Mol. Biol.2003;36:95–109.[PubMed]
40. Konat GWH2O2-induced higher order chromatin degradation: a novel mechanism of oxidative genotoxicity. J. Biosci.2003;28:57–60.[PubMed]
41. Lockwood TDRedox control of protein degradation. Antioxid. Redox Signal.2000;2:851–878.[PubMed]
42. Stadtman ER, Levine RLFree radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids.2003;25:207–218.[PubMed]
43. Sinclair DAParadigms and pitfalls of yeast longevity research. Mech. Ageing Dev.2002;123:857–867.[PubMed]
44. Lakatta EGArterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part III: cellular and molecular clues to heart and arterial aging. Circulation.2003;107:490–497.[PubMed]
45. Wallace DCMouse models for mitochondrial disease. Am. J. Med. Genet.2001;106:71–93.[PubMed]
46. Scortegagna M, et al Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1–/– mice. Nat. Genet.2003;35:331–340.[PubMed]
47. Cesselli D, et al Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ. Res.2001;89:279–286.[PubMed]
48. Ho YS, Magnenat JL, Gargano M, Cao JThe nature of antioxidant defense mechanisms: a lesson from transgenic studies. Environ. Health Perspect.1998;106(Suppl. 5):1219–1228.
49. Yen HC, Oberley TD, Vichitbandha S, Ho YS, St. Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J. Clin. Invest.1996;98:1253–1260.
50. Chen EP, Bittner HB, Davis RD, Folz RJ, Van Trigt PExtracellular superoxide dismutase transgene overexpression preserves postischemic myocardial function in isolated murine hearts. Circulation.1996;94:II412–II417.[PubMed]
51. Pennathur S, Wagner JD, Leeuwenburgh C, Litwak KN, Heinecke JWA hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease. J. Clin. Invest.2001;107:853–860.
52. Khatri JJ, et al Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma. Circulation.2004;109:520–525.[PubMed]
53. Witztum JL, Steinberg DRole of oxidized low density lipoprotein in atherogenesis. J. Clin. Invest.1991;88:1785–1792.
54. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J. Clin. Invest.1996;98:2572–2579.
55. Asimakis GK, Lick S, Patterson CPostischemic recovery of contractile function is impaired in SOD2(+/–) but not SOD1(+/–) mouse hearts. Circulation.2002;105:981–986.[PubMed]
56. Yoshida T, Maulik N, Engelman RM, Ho YS, Das DKTargeted disruption of the mouse Sod I gene makes the hearts vulnerable to ischemic reperfusion injury. Circ. Res.2000;86:264–269.[PubMed]
57. Bolli R. Causative role of oxyradicals in myocardial stunning: a proven hypothesis. A brief review of the evidence demonstrating a major role of reactive oxygen species in several forms of postischemic dysfunction. Basic Res. Cardiol.1998;93:156–162.[PubMed]
58. Perez NG, Gao WD, Marban ENovel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. Circ. Res.1998;83:423–430.[PubMed]
59. Charlat MI, et al Evidence for a pathogenetic role of xanthine oxidase in the “stunned” myocardium. Am. J. Physiol.1987;252:H566–H577.[PubMed]
60. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation.1990;81:1161–1172.[PubMed]
61. Mann DL, Spinale FGActivation of matrix metalloproteinases in the failing human heart: breaking the tie that binds. Circulation.1998;98:1699–1702.[PubMed]
62. von Harsdorf R, Li PF, Dietz RSignaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation.1999;99:2934–2941.[PubMed]
63. Engberding N, et al Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug? Circulation.2004;110:2175–2179.[PubMed]
64. Kwon SH, Pimentel DR, Remondino A, Sawyer DB, Colucci WSH(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. J. Mol. Cell. Cardiol.2003;35:615–621.[PubMed]
65. Li JM, Gall NP, Grieve DJ, Chen M, Shah AMActivation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension.2002;40:477–484.[PubMed]
66. Date MO, et al The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model. J. Am. Coll. Cardiol.2002;39:907–912.[PubMed]
67. Higuchi Y, et al Involvement of reactive oxygen species-mediated NF-kappa B activation in TNF-alpha-induced cardiomyocyte hypertrophy. J. Mol. Cell. Cardiol.2002;34:233–240.[PubMed]
68. Pimentel DR, et al Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ. Res.2001;89:453–460.[PubMed]
69. Ghosh MC, Wang X, Li S, Klee CRegulation of calcineurin by oxidative stress. Methods Enzymol.2003;366:289–304.[PubMed]
70. Gopalakrishna R, Gundimeda U, Chen ZHCancer-preventive selenocompounds induce a specific redox modification of cysteine-rich regions in Ca(2+)-dependent isoenzymes of protein kinase C. Arch. Biochem. Biophys.1997;348:25–36.[PubMed]
71. Nakamura K, et al Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation.1998;98:794–799.[PubMed]
72. Delbosc S, Cristol JP, Descomps B, Mimran A, Jover BSimvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension.2002;40:142–147.[PubMed]
73. Sugden PH, Clerk A“Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ. Res.1998;83:345–352.[PubMed]
74. Takemoto M, et al Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J. Clin. Invest.2001;108:1429–1437. doi:10.1172/JCI200113350.
75. Izumiya Y, et al Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling. Circ. Res.2003;93:874–883.[PubMed]
76. Gotoh Y, Cooper JAReactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-alpha signal transduction. J. Biol. Chem.1998;273:17477–17482.[PubMed]
77. Yamaguchi O, et al Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc. Natl. Acad. Sci. U. S. A.2003;100:15883–15888.
78. Rayment NB, et al Myocyte loss in chronic heart failure. J. Pathol.1999;188:213–219.[PubMed]
79. Adeghate EMolecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol. Cell. Biochem.2004;261:187–191.[PubMed]
80. Remondino A, et al Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ. Res.2003;92:136–138.[PubMed]
81. Kourie JIInteraction of reactive oxygen species with ion transport mechanisms. Am. J. Physiol.1998;275:C1–C24.[PubMed]
82. Guerra L, Cerbai E, Gessi S, Borea PA, Mugelli AThe effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea-pig ventricular myocytes. Br. J. Pharmacol.1996;118:1278–1284.
83. Kaplan P, Babusikova E, Lehotsky J, Dobrota DFree radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulum. Mol. Cell. Biochem.2003;248:41–47.[PubMed]
84. Nakaya H, Takeda Y, Tohse N, Kanno MMechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cells. J. Mol. Cell. Cardiol.1992;24:523–534.[PubMed]
85. Goldhaber JIFree radicals enhance Na+/Ca2+ exchange in ventricular myocytes. Am. J. Physiol.1996;271:H823–H833.[PubMed]
86. He X, et al ASK1 associates with troponin T and induces troponin T phosphorylation and contractile dysfunction in cardiomyocytes. Am. J. Pathol.2003;163:243–251.
87. Unger RHLipotoxic diseases. Annu. Rev. Med.2002;53:319–336.[PubMed]
88. Sharma S, et al Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J.2004;18:1692–1700.[PubMed]
89. Finck BN, et al A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc. Natl. Acad. Sci. U. S. A.2003;100:1226–1231.
90. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel TControl of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc. Natl. Acad. Sci. U. S. A.1993;90:347–351.
91. Bonaventura J, Gow ANO and superoxide: opposite ends of the seesaw in cardiac contractility. Proc. Natl. Acad. Sci. U. S. A.2004;101:16403–16404.
92. Khan SA, et al Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc. Natl. Acad. Sci. U. S. A.2004;101:15944–15948.
93. Gaston BM, Carver J, Doctor A, Palmer LAS-nitrosylation signaling in cell biology. Mol. Interv.2003;3:253–263.[PubMed]
94. Paolocci N, et al cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. Am. J. Physiol. Heart Circ. Physiol.2000;279:H1982–H1988.[PubMed]
95. Hare JMNitroso-redox balance in the cardiovascular system. N. Engl. J. Med.2004;351:2112–2114.[PubMed]
96. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz RPeroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ. Res.2000;87:241–247.[PubMed]
97. Taylor AL, et al Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N. Engl. J. Med.2004;351:2049–2057.[PubMed]
98. Maack C, et al Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation.2003;108:1567–1574.[PubMed]
99. Mak S, Newton GEThe oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest.2001;120:2035–2046.[PubMed]
100. Jaatinen P, Saukko P, Hervonen AChronic ethanol exposure increases lipopigment accumulation in human heart. Alcohol Alcohol.1993;28:559–569.[PubMed]
101. Mak S, Newton GERedox modulation of the inotropic response to dobutamine is impaired in patients with heart failure. Am. J. Physiol. Heart Circ. Physiol.2004;286:H789–H795.[PubMed]
102. Cappola TP, et al Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation.2001;104:2407–2411.[PubMed]
103. Doehner W, et al Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation.2002;105:2619–2624.[PubMed]
104. Rossig L, et al Vitamin C inhibits endothelial cell apoptosis in congestive heart failure. Circulation.2001;104:2182–2187.[PubMed]
105. Packer M, et al Effect of carvedilol on survival in severe chronic heart failure. N. Engl. J. Med.2001;344:1651–1658.[PubMed]
106. Hennekens CH, et al Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med.1996;334:1145–1149.[PubMed]
107. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med.2000;342:154–160.[PubMed]
108. Lonn E, et al Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care.2002;25:1919–1927.[PubMed]
109. Freudenberger RS, et al Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III - IV congestive heart failure. Expert Opin. Investig. Drugs.2004;13:1509–1516.[PubMed]
110. Giordano FJ, Johnson RSAngiogenesis: the role of the microenvironment in flipping the switch. Curr. Opin. Genet. Dev.2001;11:35–40.[PubMed]
111. Ryan HE, Lo J, Johnson RSHIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J.1998;17:3005–3015.
112. Carmeliet P, et al Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature.1998;394:485–490.[PubMed]
113. Iyer NV, et al Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev.1998;12:149–162.
114. Semenza GLHIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell.2001;107:1–3.[PubMed]
115. Kaelin WG., Jr Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer.2002;2:673–682.[PubMed]
116. Liu Q, et al A Fenton reaction at the endoplasmic reticulum is involved in the redox control of hypoxia-inducible gene expression. Proc. Natl. Acad. Sci. U. S. A.2004;101:4302–4307.
117. Cormier-Regard S, Nguyen SV, Claycomb WCAdrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J. Biol. Chem.1998;273:17787–17792.[PubMed]
118. Lee PJ, et al Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J. Biol. Chem.1997;272:5375–5381.[PubMed]
119. Semenza GLO2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. J. Appl. Physiol.2004;96:1173–1177; discussion 1170–1172.[PubMed]
120. Lee SH, et al Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N. Engl. J. Med.2000;342:626–633.[PubMed]
121. Park SK, et al Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha. Mol. Cell. Biol.2003;23:4959–4971.
122. Lei L, et al Malignant transformation of heart muscle in the absence of the von Hippel-Lindau protein. Circulation.2004;110:III–45.[PubMed]
123. Batista RJ, et al Partial left ventriculectomy to treat end-stage heart disease. Ann. Thorac. Surg.1997;64:634–638.[PubMed]
124. Gorman RC, Jackson BM, Gorman JHThe potential role of ventricular compressive therapy. Surg. Clin. North Am.2004;84:45–59.[PubMed]
125. Giordano FJ, et al A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc. Natl. Acad. Sci. U. S. A.2001;98:5780–5785.