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Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Targeting Heme Oxygenase-1 in Vascular Disease

Author(s): William Durante

Volume 11, Issue 12, 2010

Page: [1504 - 1516] Pages: 13

DOI: 10.2174/1389450111009011504

Price: $65


Heme oxygenase-1 (HO-1) metabolizes heme to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. HO-1 has recently emerged as a promising therapeutic target in the treatment of vascular disease. Pharmacological induction or gene transfer of HO-1 ameliorates vascular dysfunction in animal models of atherosclerosis, post-angioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension, while inhibition of HO-1 activity or gene deletion exacerbates these disorders. The vasoprotection afforded by HO-1 is largely attributable to its end products: CO and the bile pigments, biliverdin and bilirubin. These end products exert potent anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic actions. In addition, CO and bile pigments act to preserve vascular homeostasis at sites of arterial injury by influencing the proliferation, migration, and adhesion of vascular smooth muscle cells, endothelial cells, endothelial progenitor cells, or leukocytes. Several strategies are currently being developed to target HO-1 in vascular disease. Pharmacological induction of HO-1 by heme derivatives, dietary antioxidants, or currently available drugs, is a promising near-term approach, while HO-1 gene delivery is a long-term therapeutic goal. Direct administration of CO via inhalation or through the use of COreleasing molecules and/or CO-sensitizing agents provides an attractive alternative approach in targeting HO-1. Furthermore, delivery of bile pigments, either alone or in combination with CO, presents another avenue for protecting against vascular disease. Since HO-1 and its products are potentially toxic, a major challenge will be to devise clinically effective therapeutic modalities that target HO-1 without causing any adverse effects.

Keywords: Heme oxygenase-1, carbon monoxide, biliverdin, bilirubin, atherosclerosis, thrombosis, myocardial infarction, hypertension, carbon monoxide (CO), iron, biliverdin reductase, post-angioplasty restenosis, vein graft stenosis, vasoprotection, anti-inflammatory, antioxidant, anti-apoptotic, anti-thrombotic actions, vascular homeostasis, endothelial progenitor cells, CO-sensitizing agents, nicotinamide adenine, various metalloporphyrins, tin protoporphyin-IX, homocysteine, hemodynamic forces, nuclear factor E2-related factor-2 (Nrf2),, oxidative tissue damage, cardiovascular pathologies, atherosclerotic plaques, vulnerable pla, microsatellite polymorphism, atherogenic molecules, hypochlorous acid, Protein kinase C, apolipoprotein E (apoE), low-density lipoprotein (LDL), Bone marrow transplantation, nitric oxide (NO), intrinsic pathways, chemotaxis, tumor necrosis factor-α, granulocyte-macrophage colony, leukocyte rolling, VASCULAR OCCLUSION, angioplasty, neointimal hyperplasia, guanylate cyclase, angiogenic factors, re-endothelialization, cardiopulmonary bypass, spontaneously hypertensive rats (SHR), antihypertensive effect, deoxycorticosterone acetate (DOCA), NO synthase enzymes, smooth muscle cells (SMC), endothelial cells (EC), endothelial progenitor cells (EPC), thalassemia intermedia, myelodysplastic syndrome, erythropoietic protoporphyria, polyphenolic ingredient, a-lipoic acid, resveratrol, phytoalexin, coffee diterpenes, cafestol, kahwoel, carnosol, sulphoraphane, methionine, alanine, glutamine, postangioplasty restenosis, pentaesithrityl tetranitrate (PETN), rapamycin, paclitaxel, polymorphisms, pulmonary hypertension, intimal hyperplasia, sickle cell disease, ischemia-reperfusion injury, electrolytes, ameliorates, cytochrome P450 isozymes, dichloromethane, CO-releasing compounds (CORMs), benzyl indazole, uridine-diphosphate-glucuronosyltransferase 1A1 (UGT1A1), Metalloporphyrins, protoporphyrin, zinc protoporphyrin, chromium mesoporphyrin, small interference RNA (siRNA, inhalational gas therapy

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