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Published online before print March 6, 2008

0031-6997/08/6001-79-127$7.00
Pharmacol Rev 60:79-127, 2008

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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
I. Introduction
II. Heme Degradative Pathway
    A. Characterization of Heme Oxygenase
    B. Heme Oxygenase Isozymes
    C. Heme Oxygenase and the Heme Pool
    D. Heme Oxygenase-NADPH Biliverdin Reductase
III. Pathophysiology of and Clinical Role of Heme Oxygenase-1/Heme Oxygenase-2: Reaction Products
    A. Increased Levels of Heme Oxygenase-1 and Heme Oxygenase Activity
        1. Acute Effects.
        2. Chronic Effects.
    B. Role of Carbon Monoxide
    C. Role of Bilirubin/Biliverdin
    D. Role of Iron and Ferritin
IV. Heme Oxygenase in Disease
    A. Hypoxia and Ischemia
    B. Corneal Inflammation
    C. Hyperbilirubinemia
        1. Neonatal Jaundice.
        2. Clinical Use of Heme Oxygenase Inhibitors.
    D. Heme Oxygenase-1 in Diabetes and Obesity
    E. Heme Oxygenase-1 in Atherosclerosis
        1. Endothelial Dysfunction and Vascular Injury.
        2. Inflammation and Vascular Injury.
        3. Smooth Muscle Cell Proliferation and Vascular Injury.
        4. Vasodilatation and Vascular Function.
    F. Heme Oxygenase-1 in Myocardial Ischemia-Reperfusion Injury
    G. Cardiovascular Drugs and Drug Developments Targeting Heme Oxygenase-1 Gene Expression
        1. Aspirin.
        2. Statins.
        3. Amino Acid Apolipoprotein A-I L-4F and D-4F Mimetic Peptides.
        4. Probucol.
        5. Losartan.
        6. Paclitaxel.
        7. Rapamycin.
        8. Immunosuppressive Drugs.
        9. Curcumin.
        10. Resveratrol.
    H. Heme Oxygenase-1 and Cardiovascular Disease: Therapeutic Rationale
    I. Acute Kidney Injury and Heme Oxygenase-1/Heme Oxygenase-2
    J. Heme Oxygenase-1 and Hypertension
        1. Blood Pressure Regulation.
        2. Renovascular Hypertension.
        3. Pulmonary Hypertension.
        4. Portal Hypertension.
    K. Hepatic Injury
    L. Hormonal Regulation
    M. Stromal/Mesenchymal Stem Cells and Hematopoiesis
    N. Infectious Disease and Heme Oxygenase-1
    O. Cancer and Heme Oxygenase-1
    P. Aging, Parkinson's Disease, and Alzheimer's Disease
        1. Alzheimer's Disease.
        2. Parkinson's Disease.
    Q. Brain Hemorrhage and Heme Oxygenase System
        1. Subarachnoid Hemorrhage.
        2. Intracerebral Hemorrhage.
        3. Stroke.
V. Summary
This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

Address correspondence to: Dr. Nader G. Abraham, New York Medical College, Basic Science Building, Valhalla, NY 10595. E-mail: nader_abraham{at}nymc.edu




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