© 2000 American Heart Association, Inc.
Cellular Biology |
Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes
From the Departments of Internal Medicine, Division of Cardiology (F.J.), and Anesthesiology (L.A.P., N.Z., R.A.J.) University of Virginia Health Science Center, Charlottesville, Va; Department of Internal Medicine, Division of Cardiology (F.J.), University of Frankfurt, Germany; and Department of Anesthesiology and Critical Care (R.A.J.), The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Roger A. Johns, Professor and Chairman, Department of Anesthesiology and Critical Care, Blalock 1415, The Johns Hopkins University School of Medicine, 600 North Wolfe St, Baltimore, MD 21287-4965. E-mail rajohns{at}jhmi.edu
Abstract—The relationship between hypoxia and regulation of nitric oxide synthase (NOS) in myocardial tissue is not well understood. We investigated the role of hypoxia inducible factor-1 (HIF-1) on expression of the inducible NOS (iNOS) in myocardial cells in vivo and in vitro. In situ hybridization in myocardial tissue from rats exposed to hypoxia for 3 weeks demonstrated increased iNOS mRNA expression. Northern analysis of RNA from hearts of those animals and from cells exposed to hypoxia for 12 hours in vitro demonstrated an increase of HIF-1 RNA expression. Electrophoretic mobility shift assays using oligonucleotides containing the iNOS HIF-1 DNA binding site and nuclear extracts from cardiac myocytes showed induction of specific DNA binding in cells subjected to hypoxia. Transient transfection of cardiac myocytes using the murine iNOS promoter resulted in a 3.43-fold increase in promoter activity under hypoxia compared with normoxia. Mutation or deletion of the HIF-1 site eliminated the hypoxic response. As cytokines have been shown to regulate iNOS expression in myocardial cells, cultured neonatal cardiac myocytes were stimulated with interleukin-1ß causing a dramatic induction of iNOS protein expression under normoxia, with further augmentation under hypoxia. Transient transfection of cells stimulated with interleukin-1ß showed an increased iNOS promoter activity under normoxic conditions compared with unstimulated cells, with a further increase in response to hypoxia, which was dependent on HIF-1. These results demonstrate that hypoxia causes an increase in iNOS expression in cardiac myocytes and that HIF-1 is essential for the hypoxic regulation of iNOS gene expression.
Key Words: inducible nitric oxide synthase • hypoxia inducible factor-1 • heart • hypoxia
This article has been cited by other articles:
 |
|
 |
|
  J. F. Garvey, C. T. Taylor, and W. T. McNicholas Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation Eur. Respir. J., May 1, 2009; 33(5): 1195 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Martin and J Windsor From mountain to bedside: understanding the clinical relevance of human acclimatisation to high-altitude hypoxia Postgrad. Med. J., December 1, 2008; 84(998): 622 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Cowley Jr Renal Medullary Oxidative Stress, Pressure-Natriuresis, and Hypertension Hypertension, November 1, 2008; 52(5): 777 - 786. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garedew and S. Moncada Mitochondrial dysfunction and HIF1{alpha} stabilization in inflammation J. Cell Sci., October 15, 2008; 121(20): 3468 - 3475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu and S. A. Fisher Hypoxia-Inducible Transcription Factor-1{alpha} Triggers an Autocrine Survival Pathway During Embryonic Cardiac Outflow Tract Remodeling Circ. Res., June 6, 2008; 102(11): 1331 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, L. Chen, F. Yi, M. Xia, and P.-L. Li Salt-Sensitive Hypertension Induced by Decoy of Transcription Factor Hypoxia-Inducible Factor-1{alpha} in the Renal Medulla Circ. Res., May 9, 2008; 102(9): 1101 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Robinson, J. E. Baumgardner, V. P. Good, and C. M. Otto Physiological and hypoxic O2 tensions rapidly regulate NO production by stimulated macrophages Am J Physiol Cell Physiol, April 1, 2008; 294(4): C1079 - C1087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Belaidi, P. C. Beguin, P. Levy, C. Ribuot, and D. Godin-Ribuot Prevention of HIF-1 activation and iNOS gene targeting by low-dose cadmium results in loss of myocardial hypoxic preconditioning in the rat Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H901 - H908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liao, M. C. Hyman, D. A. Lawrence, and D. J. Pinsky Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1{alpha}, and C/EBP{alpha} FASEB J, March 1, 2007; 21(3): 935 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. S. Hwang, M. L. Fung, E. C. Liong, G. L. Tipoe, and F. Tang Age-Related Changes in Adrenomedullin Expression and Hypoxia-Inducible Factor-1 Activity in the Rat Lung and Their Responses to Hypoxia J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2007; 62(1): 41 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li, F. Yi, C. M. Sundy, L. Chen, M. L. Hilliker, D. K. Donley, D. B. Muldoon, and P.-L. Li Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys Am J Physiol Renal Physiol, January 1, 2007; 292(1): F207 - F216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Dong and L. P. Thompson Differential Expression of Endothelial Nitric Oxide Synthase in Coronary and Cardiac Tissue in Hypoxic Fetal Guinea Pig Hearts Reproductive Sciences, October 1, 2006; 13(7): 483 - 490. [Abstract] [PDF]
|
|
|
|
|
|
M. Zampino, M. Yuzhakova, J. Hansen, R. D. McKinney, P. H. Goldspink, D. L. Geenen, and P. M. Buttrick Sex-related dimorphic response of HIF-1{alpha} expression in myocardial ischemia Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H957 - H964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Philipp, J. S. Jurgensen, J. Fielitz, W. M. Bernhardt, A. Weidemann, A. Schiche, B. Pilz, R. Dietz, V. Regitz-Zagrosek, K.-U. Eckardt, et al. Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats Eur J Heart Fail, June 1, 2006; 8(4): 347 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, R. Kohl, B. Herr, R. Frank, and B. Brune Calpain Mediates a von Hippel-Lindau Protein-independent Destruction of Hypoxia-inducible Factor-1{alpha} Mol. Biol. Cell, April 1, 2006; 17(4): 1549 - 1558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Depre, L. Wang, X. Sui, H. Qiu, C. Hong, N. Hedhli, A. Ginion, A. Shah, M. Pelat, L. Bertrand, et al. H11 Kinase Prevents Myocardial Infarction by Preemptive Preconditioning of the Heart Circ. Res., February 3, 2006; 98(2): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Lefer Induction of HIF-1{alpha} and iNOS With siRNA: A Novel Mechanism for Myocardial Protection Circ. Res., January 6, 2006; 98(1): 10 - 11. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kido, L. Du, C. C. Sullivan, X. Li, R. Deutsch, S. W. Jamieson, and P. A. Thistlethwaite Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2116 - 2124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Staib, A. I. Robles, L. Varticovski, X. W. Wang, B. R. Zeeberg, M. Sirotin, V. B. Zhurkin, L. J. Hofseth, S. P. Hussain, J. N. Weinstein, et al. The p53 Tumor Suppressor Network Is a Key Responder to Microenvironmental Components of Chronic Inflammatory Stress Cancer Res., November 15, 2005; 65(22): 10255 - 10264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. Thompson and Y. Dong Chronic Hypoxia Decreases Endothelial Nitric Oxide Synthease Protein Expression in Fetal Guinea Pig Hearts Reproductive Sciences, September 1, 2005; 12(6): 388 - 395. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Navarro-Antolin, K. L. Levitsky, E. Calderon, A. Ordonez, and J. Lopez-Barneo Decreased Expression of Maxi-K+ Channel {beta}1-Subunit and Altered Vasoregulation in Hypoxia Circulation, August 30, 2005; 112(9): 1309 - 1315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Dawn and R. Bolli HO-1 induction by HIF-1: a new mechanism for delayed cardioprotection? Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H522 - H524. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Zhan, P. Fenik, D. Pratico, and S. C. Veasey Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia: Hypersomnolence and Brain Injury Am. J. Respir. Crit. Care Med., June 15, 2005; 171(12): 1414 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kaur, F. W. Khwaja, E. A. Severson, S. L. Matheny, D. J. Brat, and E. G. Van Meir Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis Neuro-oncol, April 1, 2005; 7(2): 134 - 153. [Abstract] [PDF]
|
|
|
|
|
|
T. Date, S. Mochizuki, A. J. Belanger, M. Yamakawa, Z. Luo, K. A. Vincent, S. H. Cheng, R. J. Gregory, and C. Jiang Expression of constitutively stable hybrid hypoxia-inducible factor-1{alpha} protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury Am J Physiol Cell Physiol, February 1, 2005; 288(2): C314 - C320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Morita, K. Iizuka, K. Okita, T. Oikawa, K. Yonezawa, T. Nagai, Y. Tokumitsu, T. Murakami, A. Kitabatake, and H. Kawaguchi Exposure to pressure stimulus enhances succinate dehydrogenase activity in L6 myoblasts Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1064 - E1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xi, M. Taher, C. Yin, F. Salloum, and R. C. Kukreja Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1{alpha} and AP-1 and iNOS signaling Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2369 - H2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Tsai, M. Wang, M. Clauss, P. Sun, and D. R. Meldrum Endothelial monocyte-activating polypeptide II causes NOS-dependent pulmonary artery vasodilation: a novel effect for a proinflammatory cytokine Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R767 - R771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A Bogoyevitch An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection Cardiovasc Res, August 1, 2004; 63(2): 208 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Azadzoi, T. A. Master, and M. B. Siroky Effect of Chronic Ischemia on Constitutive and Inducible Nitric Oxide Synthase Expression in Erectile Tissue J Androl, May 1, 2004; 25(3): 382 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schlieper, J.-H. Kim, A. Molojavyi, C. Jacoby, T. Laussmann, U. Flogel, A. Godecke, and J. Schrader Adaptation of the myoglobin knockout mouse to hypoxic stress Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R786 - R792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Welsh, R. Williams, L. Kirkpatrick, G. Paine-Murrieta, and G. Powis Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1{alpha} Mol. Cancer Ther., March 1, 2004; 3(3): 233 - 244. [Abstract] [Full Text]
|
|
|
|
|
|
K. S. Mark, A. R. Burroughs, R. C. Brown, J. D. Huber, and T. P. Davis Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H174 - H180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.W. Boots, G.R.M.M. Haenen, and A. Bast Oxidant metabolism in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 14s - 27s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-F. Chen, S.-Y. Tsai, M.-C. Ma, and M.-S. Wu Hypoxic preconditioning enhances renal superoxide dismutase levels in rats J. Physiol., October 15, 2003; 552(2): 561 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Lukiw, A. Ottlecz, G. Lambrou, M. Grueninger, J. Finley, H. W. Thompson, and N. G. Bazan Coordinate Activation of HIF-1 and NF-{kappa}B DNA Binding and COX-2 and VEGF Expression in Retinal Cells by Hypoxia Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4163 - 4170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Grilli, M. A. De Lutiis, A. Patruno, L. Speranza, A. Cataldi, L. Centurione, A. A. Taccardi, P. Di Napoli, R. De Caterina, R. Barbacane, et al. Effect of Chronic Hypoxia on Inducible Nitric Oxide Synthase Expression in Rat Myocardial Tissue Experimental Biology and Medicine, September 1, 2003; 228(8): 935 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Wright, J. J. Higgin, R. T. Raines, C. Steenbergen, and E. Murphy Activation of the Prolyl Hydroxylase Oxygen-sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes J. Biol. Chem., May 23, 2003; 278(22): 20235 - 20239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Grilli, M. A. De Lutiis, A. Patruno, L. Speranza, F. Gizzi, A. A. Taccardi, P. Di Napoli, R. De Caterina, P. Conti, and M. Felaco Inducible Nitric Oxide Synthase and Heme Oxygenase-1 in Rat Heart: Direct Effect of Chronic Exposure to Hypoxia Ann. Clin. Lab. Sci., April 1, 2003; 33(2): 208 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xi, D. Tekin, E. Gursoy, F. Salloum, J. E. Levasseur, and R. C. Kukreja Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H5 - H12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Teng, D. Li, J. D. Catravas, and R. A. Johns C/EBP-{beta} Mediates iNOS Induction by Hypoxia in Rat Pulmonary Microvascular Smooth Muscle Cells Circ. Res., February 8, 2002; 90(2): 125 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Kim, Y.-S. Cho, Y.-S. Chun, J.-W. Park, and M.-S. Kim Early Expression of Myocardial HIF-1{alpha} in Response to Mechanical Stresses: Regulation by Stretch-Activated Channels and the Phosphatidylinositol 3-Kinase Signaling Pathway Circ. Res., February 8, 2002; 90 (2): e25 - e33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Li and R. M. Jackson Reactive species mechanisms of cellular hypoxia-reoxygenation injury Am J Physiol Cell Physiol, February 1, 2002; 282(2): C227 - C241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Pitt and C. M. St. Croix Complex Regulation of iNOS in Lung Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 6 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Iglarz, J.-S. Silvestre, M. Duriez, D. Henrion, and B. I. Levy Chronic Blockade of Endothelin Receptors Improves Ischemia-Induced Angiogenesis in Rat Hindlimbs Through Activation of Vascular Endothelial Growth Factor-NO Pathway Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1598 - 1603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Pearl, D. P. Nelson, C. J. Wagner, J. P. Lombardi, and J. Y. Duffy Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation Ann. Thorac. Surg., August 1, 2001; 72(2): 565 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Ferreiro, A. C. P. Chagas, M. H. C. Carvalho, A. P. Dantas, M. B. Jatene, L. C. Bento de Souza, and P. Lemos da Luz Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease : A Novel Pathophysiological Adaptive Mechanism Circulation, May 8, 2001; 103(18): 2272 - 2276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Semenza HIF-1 and human disease: one highly involved factor Genes & Dev., August 15, 2000; 14(16): 1983 - 1991. [Full Text]
|
|
|
|
|
|
X. Teng, D. Li, J. D. Catravas, and R. A. Johns C/EBP-{beta} Mediates iNOS Induction by Hypoxia in Rat Pulmonary Microvascular Smooth Muscle Cells Circ. Res., February 8, 2002; 90(2): 125 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Kim, Y.-S. Cho, Y.-S. Chun, J.-W. Park, and M.-S. Kim Early Expression of Myocardial HIF-1{alpha} in Response to Mechanical Stresses: Regulation by Stretch-Activated Channels and the Phosphatidylinositol 3-Kinase Signaling Pathway Circ. Res., February 8, 2002; 90 (2): e25 - e33. [Abstract] [Full Text] [PDF]
|
|