Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO) catalyzes the degradation of heme to CO, iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although long considered irrelevant byproducts of heme catabolism, recent studies indicate that CO and the bile pigments biliverdin and bilirubin may play an important physiological role in the circulation. The release of CO by vascular cells may modulate blood flow and blood fluidity by inhibiting vasomotor tone, smooth muscle cell proliferation, and platelet aggregation. CO may also maintain the integrity of the vessel wall by directly blocking vascular cell apoptosis and by inhibiting the release of pro-apoptotic inflammatory cytokines from the vessel wall. These effects of CO are mediated via multiple pathways, including activation of soluble guanylate cyclase, potassium channels, p38 mitogen-activated protein kinase, or inhibition of cytochrome P450. In addition, the release of bile pigments may serve to sustain vascular homeostasis by protecting vascular cells from oxidative stress and by inhibiting the adhesion and infiltration of leukocytes into the vessel wall. Induction of HO-1 gene expression and the subsequent release of CO and bile pigments are observed in numerous vascular disorders and may provide an important adaptive mechanism to preserve homeostasis at sites of vascular injury. Thus, the HO-catalyzed formation of CO and bile pigments by vascular cells may function as a critical endogenous vasoprotective system. Moreover, pharmacological or genetic approaches targeting HO-1 to the vessel wall may represent a novel therapeutic approach in treating vascular disease.
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PMID:Carbon monoxide and bile pigments: surprising mediators of vascular function. 1255 43

Walnut consumption is associated with reduced coronary vascular disease (CVD) risk; however, the mechanisms responsible remain incompletely understood. Recent clinical studies suggested that these mechanisms involve non-plasma lipid-related effects on endothelial function. Male Golden Syrian hamsters (12 groups, n=10-15) were fed for 26 wk atherosclerotic, high-fat, hyperlipidemic diets with increasing concentrations of whole walnuts (61-150 g/kg diet), or alpha-tocopherol (alpha-T, 8.1-81 mg/kg diet) and single diets with either walnut oil (32 g/kg diet) or pure gamma-tocopherol (gamma-T; 81 mg/kg diet) added. Aortic endothelin 1 (ET-1), an important endothelial regulator, was assayed as mRNA. Aortic cholesterol ester (CE) concentration along with other vascular stress markers (Cu/Zn and Mn superoxide dismutase, biliverdin reductase) and plasma lipid concentrations were determined. Hyperlipidemia (plasma LDL cholesterol approximately 6 times normal) occurred in all groups. Aortic CE concentration, a measure of atherosclerotic plaque, was highest in the lowest alpha-T only group and declined significantly with increasing alpha-T. The aortic CE of all walnut groups was decreased significantly relative to the lowest alpha-T only group but showed no dose response. The diets did not produce changes in the other vascular stress markers, whereas aortic ET-1 mRNA levels declined dramatically with increasing dietary walnuts (to a 75% reduction in the highest walnut content group compared with the lowest alpha-T group) but were unaltered in the alpha-T groups or gamma-T group. The study results are consistent with those of human walnut feeding studies and suggest that the mechanisms underlying those results are mediated in part by ET-1-dependent mechanisms. The contrasting results between the alpha-tocopherol or gamma-tocopherol diets and the walnut diets also make it unlikely that the non-plasma lipid-related CVD effects of walnuts are due to their alpha-tocopherol or gamma-tocopherol content. Finally, the results indicate that the walnut fat compartment is a likely location for the components responsible for the reduced aortic CE concentration.
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PMID:Walnuts reduce aortic ET-1 mRNA levels in hamsters fed a high-fat, atherogenic diet. 1642 23

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 CO-releasing 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.
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PMID:Targeting heme oxygenase-1 in vascular disease. 2070 50

Bilirubin is a heme metabolite generated by the concerted action of the enzymes heme oxygenase and biliverdin reductase. Although long considered a toxic byproduct of heme catabolism, recent preclinical, and clinical studies indicate the bilirubin exerts beneficial effects in the circulation. In the present study, we determined whether local administration of bilirubin attenuates neointima formation following injury of rat carotid arteries. In addition, the ability of bilirubin to regulate the proliferation and migration of human arterial smooth muscle cells (SMCs) was investigated. Local perivascular administration of bilirubin immediately following balloon injury of rat carotid arteries significantly attenuated neointima formation. Bilirubin-mediated inhibition of neointimal thickening was associated with a significant decrease in ERK activity and cyclin D1 and A protein expression, and an increase in p21 and p53 protein expression in injured blood vessels. Treatment of human aortic SMCs with bilirubin inhibited proliferation and migration in a concentration-dependent manner without affecting cell viability. In addition, bilirubin resulted in a concentration-dependent increase in the percentage of cells in the G(0)/G(1) phase of the cell cycle and this was paralleled by a decrease in the fraction of cells in the S and G(2)M phases of the cell cycle. Finally, bilirubin had no effect on mitochondrial function and ATP content of vascular SMCs. In conclusion, these studies demonstrate that bilirubin inhibits neointima formation after arterial injury and this is associated with alterations in the expression of cell cycle regulatory proteins. Furthermore, bilirubin blocks proliferation and migration of human arterial SMCs and arrests SMCs in the G(0)/G(1) phase of the cell cycle. Bilirubin represents an attractive therapeutic agent in treating occlusive vascular disease.
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PMID:Bilirubin inhibits neointima formation and vascular smooth muscle cell proliferation and migration. 2247 Mar 41

The global epidemic of obesity continues unabated with sequelae of diabetes and metabolic syndrome. This review reflects the dramatic increase in research on the role of increased expression of heme oxygenase (HO)-1/HO-2, biliverdin reductase, and HO activity on vascular disease. The HO system engages with other systems to mitigate the deleterious effects of oxidative stress in obesity and cardiovascular disease (CVD). Recent reports indicate that HO-1/HO-2 protein expression and HO activity have several important roles in hemostasis and reactive oxygen species (ROS)-dependent perturbations associated with metabolic syndrome. HO-1 protects tissue during inflammatory stress in obesity through the degradation of pro-oxidant heme and the production of carbon monoxide (CO) and bilirubin, both of which have anti-inflammatory and anti-apoptotic properties. By contrast, repression of HO-1 is associated with increases of cellular heme and inflammatory conditions including hypertension, stroke, and atherosclerosis. HO-1 is a major focus in the development of potential therapeutic strategies to reverse the clinical complications of obesity and metabolic syndrome.
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PMID:Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome. 2651 32