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Pharmacological and Clinical Aspects of Heme Oxygenase

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Pharmacological and Clinical Aspects of Heme Oxygenase Supplemental Material can be found at: http://pharmrev.aspetjournals.org/cgi/content/full/pr.107.07104/DC1 0031-6997/08/6001-79–127$20.00 PHARMACOLOGICAL REVIEWS Vol. 60, No. 1 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 7104/3331534 Pharmacol Rev 60:79–127, 2008 Printed in U.S.A Pharmacological and Clinical Aspects of Heme Oxygenase NADER G. ABRAHAM AND ATTALLAH KAPPAS New York Medical College, Department of Pharmacology and Medicine, Valhalla, New York (N.G.A.); and Rockefeller University Hospital, New York, New York (N.G.A., A.K.) Abstract ................................................................................ 80 I. Introduction ............................................................................. 80 II. Heme degradative pathway ............................................................... 81 A. Characterization of heme oxygenase .................................................... 81 Downloaded from B. Heme oxygenase isozymes ............................................................. 81 C. Heme oxygenase and the heme pool .................................................... 83 D. Heme oxygenase-NADPH-biliverdin reductase ........................................... 84 III. Pathophysiology of and clinical role of heme oxygenase-1/heme oxygenase-2: reaction products . 84 A. Increased levels of heme oxygenase-1 and heme oxygenase activity ........................ 84 pharmrev.aspetjournals.org 1. Acute effects ..................................................................... 84 2. Chronic effects ................................................................... 85 B. Role of carbon monoxide............................................................... 85 C. Role of bilirubin/biliverdin ............................................................. 87 D. Role of iron and ferritin ............................................................... 89 IV. Heme oxygenase in disease ............................................................... 89 A. Hypoxia and ischemia................................................................. 89 B. Corneal inflammation ................................................................. 90 at University of Toledo Libraries on October 23, 2009 C. Hyperbilirubinemia ................................................................... 91 1. Neonatal jaundice ................................................................ 91 2. Clinical use of heme oxygenase inhibitors ........................................... 91 D. Heme oxygenase-1 in diabetes and obesity .............................................. 91 E. Heme oxygenase-1 in atherosclerosis ................................................... 94 1. Endothelial dysfunction and vascular injury......................................... 95 2. Inflammation and vascular injury .................................................. 96 3. Smooth muscle cell proliferation and vascular injury ................................. 96 4. Vasodilatation and vascular function ............................................... 97 F. Heme oxygenase-1 in myocardial ischemia-reperfusion injury ............................. 97 G. Cardiovascular drugs and drug development targeting heme oxygenase-1 gene expression . 98 1. Aspirin .......................................................................... 99 2. Statins .......................................................................... 99 3. Amino acid apolipoprotein A-I L-4F and D-4F mimetic peptides ...................... 100 4. Probucol ........................................................................ 100 5. Losartan........................................................................ 100 6. Paclitaxel ....................................................................... 101 7. Rapamycin...................................................................... 101 8. Immunosuppressive drugs ........................................................ 101 9. Curcumin ....................................................................... 101 10. Resveratrol ..................................................................... 101 H. Heme oxygenase-1 and cardiovascular disease: therapeutic rationale ..................... 101 I. Acute kidney injury and heme oxygenase-1/heme oxygenase-2 ........................... 102 J. Heme oxygenase-1 and hypertension .................................................. 103 1. Blood pressure regulation ........................................................ 103 2. Renovascular hypertension ....................................................... 104 Address correspondence to: Dr. Nader G. Abraham, New York Medical College, Basic Science Building, Valhalla, NY 10595. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.107.07104. 79 80 ABRAHAM AND KAPPAS 3. Pulmonary hypertension ......................................................... 105 4. Portal hypertension .............................................................. 105 K. Hepatic injury....................................................................... 105 L. Hormonal regulation................................................................. 107 M. Stromal/mesenchymal stem cells and hematopoiesis .................................... 108 N. Infectious disease and heme oxygenase-1 .............................................. 109 O. Cancer and heme oxygenase-1 ........................................................ 110 P. Aging, Parkinson’s disease, and Alzheimer’s disease .................................... 112 1. Alzheimer’s disease .............................................................. 114 2. Parkinson’s disease .............................................................. 115 Q. Brain hemorrhage and heme oxygenase system......................................... 115 1. Subarachnoid hemorrhage ........................................................ 115 2. Intracerebral hemorrhage ........................................................ 115 3. Stroke .......................................................................... 116 Downloaded from V. Summary .............................................................................. 116 Acknowledgments....................................................................... 116 References ............................................................................. 116 pharmrev.aspetjournals.org Abstract——This review is intended to stimulate in- This review focuses on the clinical potential of in- terest in the effect of increased expression of heme creased levels of HO-1 protein and HO activity to ame- oxygenase-1 (HO-1) protein and increased levels of HO liorate tissue injury. The use of pharmacological and activity on normal and pathological states. The HO genetic probes to manipulate HO, leading to new in- system includes the heme catabolic pathway, compris- sights into the complex relationship of the HO system ing HO and biliverdin reductase, and the products of with biological and pathological phenomena under in- heme degradation, carbon monoxide (CO), iron, and vestigation, is reviewed. This information is critical in biliverdin/bilirubin. The role of the HO system in dia- both drug development and the implementation of betes, inflammation, heart disease, hypertension, neu- clinical approaches to moderate and to alleviate the at University of Toledo Libraries on October 23, 2009 rological disorders, transplantation, endotoxemia and numerous chronic disorders in humans affected by other pathologies is a burgeoning area of research. perturbations in the HO system. I. Introduction of equimolar amounts of the bile pigment biliverdin, free iron, and carbon monoxide (CO). Biliverdin formed in Heme oxygenase (HO1) is the rate-limiting enzyme in this reaction is rapidly converted to bilirubin. The enzy- the catabolism of heme, a process that leads to formation matic nature of the heme catabolic process and the es- 1Abbreviations: HO, heme oxygenase; CO, carbon monoxide; sential features of its biochemistry were initially de- HO-1, heme oxygenase isozyme 1 (inducible form); HO-2, heme ox- scribed by the Schmid group (Tenhunen et al., 1968, ygenase isozyme 2 (constitutive form); ALA, ␦-aminolevulinic acid; Ϫ 1970). Similarities of this process to the cytochrome O2 ; AP-1, activator protein-1; PKC, protein kinase C; SnCl2, stan- nous chloride; HETE, hydroxyeicosatetraenoic acid; COX, cyclooxy- P450-dependent mixed function oxidase system, which genase; SnMP, tin mesoporphyrin IX dichloride; CoPP, cobalt proto- had been earlier described by Estabrook and colleagues porphyrin IX dichloride; NOD, nonobese diabetic; CoCl2, cobaltous (Estabrook et al., 1963; Cooper et al., 1965), subse- chloride; eNOS, endothelial nitric-oxide synthase; AKT, protein ki- quently led to the proposed role of cytochrome P450 as nase (activator); p, phosphorylated; NO, nitric oxide; NOS, nitric- the terminal oxidase in the heme catabolic system (Ten- oxide synthase; ZnPP, zinc protoporphyrin IX dichloride; YC-1, 3-(5Ј- hydroxymethyl-2Ј-furyl)-1-benzyl indazole; SHR, spontaneously hunen et al., 1972). However, the disparity in organ hypertensive rats; ZnDP, zinc 2,4-bis glycol deuteroporphyrin; NTS, distribution and tissue concentrations of cytochrome nucleus of the tractus solitarius; BKCa channel, large-conductance P450 and the HO system, among other considerations, calcium-activated potassium channel; CORM, carbon monoxide re- leasing molecule; sGC,
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