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PMID: 10207174 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice.

The Journal of clinical investigation ·Vol. 103 ·No. 8 ·1999-04-00 ·Pages R23-9

Yet SF, Perrella MA, Layne MD, Hsieh CM, Maemura K, Kobzik L, Wiesel P, Christou H, Kourembanas S, Lee ME

Abstract

Heme oxygenase (HO) catalyzes the oxidation of heme to generate carbon monoxide (CO) and bilirubin. CO increases cellular levels of cGMP, which regulates vascular tone and smooth muscle development. Bilirubin is a potent antioxidant. Hypoxia increases expression of the inducible HO isoform (HO-1) but not the constitutive isoform (HO-2). To determine whether HO-1 affects cellular adaptation to chronic hypoxia in vivo, we generated HO-1 null (HO-1(-/-)) mice and subjected them to hypoxia (10% oxygen) for five to seven weeks. Hypoxia caused similar increases in right ventricular systolic pressure in wild-type and HO-1(-/-) mice. Although ventricular weight increased in wild-type mice, the increase was greater in HO-1(-/-) mice. Similarly, the right ventricles were more dilated in HO-1(-/-) mice. After seven weeks of hypoxia, only HO-1(-/-) mice developed right ventricular infarcts with organized mural thrombi. No left ventricular infarcts were observed. Lipid peroxidation and oxidative damage occurred in right ventricular cardiomyocytes in HO-1(-/-), but not wild-type, mice. We also detected apoptotic cardiomyocytes surrounding areas of infarcted myocardium by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assays. Our data suggest that in the absence of HO-1, cardiomyocytes have a maladaptive response to hypoxia and subsequent pulmonary hypertension. J.Clin. Invest. 103:R23-R29 (1999).

MeSH Terms
Animals Dilatation, Pathologic Female Heme Oxygenase (Decyclizing)/genetics,physiology Heme Oxygenase-1 Hypoxia Male Membrane Proteins Mice Mice, Inbred BALB C Mice, Inbred C57BL Myocardial Infarction/etiology Organ Size Ventricular Dysfunction, Left/etiology Ventricular Pressure
Chemicals
Membrane Proteins Heme Oxygenase (Decyclizing) Heme Oxygenase-1 Hmox1 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Yet S F
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Perrella M A
Layne M D
Hsieh C M
Maemura K
Kobzik L
Wiesel P
Christou H
Kourembanas S
Lee M E
References (49)
49 references, click to expand
  1. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3.
    Eur J Biochem. 1997 Jul 15;247(2):725-32 PMID: 9266719
  2. Defective smooth muscle regulation in cGMP kinase I-deficient mice.
    EMBO J. 1998 Jun 1;17(11):3045-51 PMID: 9606187
  3. Heme oxygenase 1 is required for mammalian iron reutilization.
    Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24 PMID: 9380735
  4. Reduced stress defense in heme oxygenase 1-deficient cells.
    Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30 PMID: 9380736
  5. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells.
    J Biol Chem. 1997 Dec 26;272(52):32804-9 PMID: 9407056
  6. Induction of HSP 32 gene in hypoxic cardiomyocytes is attenuated by treatment with N-acetyl-L-cysteine.
    Am J Physiol. 1998 Mar;274(3 Pt 2):H965-73 PMID: 9530210
  7. Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3.
    J Clin Invest. 1998 Jun 1;101(11):2468-77 PMID: 9616218
  8. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension.
    Am J Respir Cell Mol Biol. 1998 Jun;18(6):768-76 PMID: 9618381
  9. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes.
    J Biol Chem. 1998 Jul 17;273(29):18092-8 PMID: 9660766
  10. Induction of heme oxygenase-1 during endotoxemia is downregulated by transforming growth factor-beta1.
    Circ Res. 1998 Aug 24;83(4):396-403 PMID: 9721696
  11. Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 is not essential for this enzyme activity.
    Proc Natl Acad Sci U S A. 1974 Nov;71(11):4293-7 PMID: 4530983
  12. Lung vascular smooth muscle as a determinant of pulmonary hypertension at high altitude.
    Am J Physiol. 1975 Mar;228(3):762-7 PMID: 234690
  13. Resolution of pulmonary hypertension and other features induced by chronic hypoxia in rats during complete and intermittent normoxia.
    Thorax. 1978 Aug;33(4):468-73 PMID: 151344
  14. Ultrastructural findings in lung biopsy material from children with congenital heart defects.
    Am J Pathol. 1980 Dec;101(3):527-42 PMID: 7446706
  15. Impairment of hypoxic pulmonary artery remodeling by heparin in mice.
    Am Rev Respir Dis. 1983 Oct;128(4):747-51 PMID: 6226226
  16. Cloning and expression of cDNA for rat heme oxygenase.
    Proc Natl Acad Sci U S A. 1985 Dec;82(23):7865-9 PMID: 3865203
  17. Purification and characterization of the major constitutive form of testicular heme oxygenase. The noninducible isoform.
    J Biol Chem. 1986 Aug 25;261(24):11131-7 PMID: 3525562
  18. Bilirubin is an antioxidant of possible physiological importance.
    Science. 1987 Feb 27;235(4792):1043-6 PMID: 3029864
  19. Antioxidant activity of albumin-bound bilirubin.
    Proc Natl Acad Sci U S A. 1987 Aug;84(16):5918-22 PMID: 3475708
  20. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase.
    Mol Pharmacol. 1987 Oct;32(4):497-504 PMID: 2890093
  21. Left ventricular thrombus formation after first anterior wall acute myocardial infarction.
    Am J Cardiol. 1988 Jul 1;62(1):31-5 PMID: 3381753
  22. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications.
    FASEB J. 1988 Jul;2(10):2557-68 PMID: 3290025
  23. Multiplicity of heme oxygenase isozymes. HO-1 and HO-2 are different molecular species in rat and rabbit.
    J Biol Chem. 1989 Jan 15;264(2):1323-8 PMID: 2910857
  24. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits.
    Arteriosclerosis. 1990 May-Jun;10(3):336-49 PMID: 1693069
  25. Oxidative changes in hypoxic-reoxygenated rabbit heart: a consequence of hypoxia rather than reoxygenation.
    Free Radic Res Commun. 1991;14(3):179-85 PMID: 2060863
  26. Oxidative stress during hypoxia in isolated-perfused rat heart.
    Adv Exp Med Biol. 1991;283:299-304 PMID: 2069001
  27. Left ventricular thrombus in anterior acute myocardial infarction after thrombolysis. A GISSI-2 connected study.
    Circulation. 1991 Aug;84(2):512-9 PMID: 1860196
  28. Simplified mammalian DNA isolation procedure.
    Nucleic Acids Res. 1991 Aug 11;19(15):4293 PMID: 1870982
  29. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
    J Cell Biol. 1992 Nov;119(3):493-501 PMID: 1400587
  30. Separate regulation of heme oxygenase and heat shock protein 70 mRNA expression in the rat heart by hemodynamic stress.
    Biochem Biophys Res Commun. 1993 Mar 15;191(2):587-94 PMID: 8461015
  31. Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP.
    J Appl Physiol (1985). 1993 Jul;75(1):198-205 PMID: 7690745
  32. Isolation and characterization of the mouse heme oxygenase-1 gene. Distal 5' sequences are required for induction by heme or heavy metals.
    J Biol Chem. 1994 Jan 14;269(2):1001-9 PMID: 8288554
  33. Cyclic GMP: synthesis, metabolism, and function. Introduction and some historical comments.
    Adv Pharmacol. 1994;26:1-5 PMID: 8038102
  34. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system.
    Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):850-4 PMID: 7846065
  35. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1475-9 PMID: 7878003
  36. Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation.
    Am J Respir Cell Mol Biol. 1995 Oct;13(4):387-98 PMID: 7546768
  37. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats.
    Am J Pathol. 1996 Jan;148(1):291-300 PMID: 8546218
  38. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.
    Am J Respir Cell Mol Biol. 1996 Jul;15(1):9-19 PMID: 8679227
  39. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide.
    J Clin Invest. 1995 Dec;96(6):2676-82 PMID: 8675634
  40. Coordinated expression of heme oxygenase-1 and ubiquitin in the porcine heart subjected to ischemia and reperfusion.
    Mol Cell Biochem. 1996 Apr 12-26;157(1-2):111-6 PMID: 8739236
  41. NO-mediated activation of heme oxygenase: endogenous cytoprotection against oxidative stress to endothelium.
    Am J Physiol. 1996 Jan;270(1 Pt 2):H107-14 PMID: 8769740
  42. Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia.
    Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10393-8 PMID: 8816811
  43. Induction of heme oxygenase-1 expression in vascular smooth muscle cells. A link to endotoxic shock.
    J Biol Chem. 1997 Feb 14;272(7):4295-301 PMID: 9020147
  44. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.
    J Biol Chem. 1997 Feb 28;272(9):5375-81 PMID: 9038135
  45. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium.
    J Mol Cell Cardiol. 1997 Jan;29(1):207-16 PMID: 9040035
  46. The heme oxygenase system: a regulator of second messenger gases.
    Annu Rev Pharmacol Toxicol. 1997;37:517-54 PMID: 9131263
  47. Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells.
    J Clin Invest. 1997 Aug 1;100(3):589-96 PMID: 9239406
  48. Chronic hypoxia-induced cardiopulmonary changes in three rat strains: inhibition by the endothelin receptor antagonist SB 217242.
    J Cardiovasc Pharmacol. 1998;31 Suppl 1:S453-5 PMID: 9595510
  49. Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction.
    Circulation. 1997 Oct 7;96(7):2414-20 PMID: 9337218
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI6163
Published
1999-04-00
Pages
R23-9
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC408281
Subset
IM
Grants
NHLBI NIH HHS · F32 HL010113 · United States
NHLBI NIH HHS · HL-53249 · United States
NHLBI NIH HHS · HL-10113 · United States
NHLBI NIH HHS · HL-60788 · United States
NHLBI NIH HHS · R01 HL060788 · United States
NHLBI NIH HHS · R01 HL055454 · United States
External Links
PubMed source DOI: 10.1172/JCI6163 PMC Full Text View journal details
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