Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bilirubin is an endogenous antioxidant and is the end product of heme catabolism by heme oxygenase (HO) and biliverdin reductase. Chronic angiotensin II (Ang II) infusion induces renal HO-1 expression that is associated with renoprotective effects, and further induction of renal HO-1 attenuates the development of hypertension in this model. To determine the effects of bilirubin on the development of Ang II-induced hypertension and resultant proteinuria, 2 groups of rats were studied: Ang II (n = 4) and Ang II + bilirubin (n = 4). Rats were infused with Ang II (80 ng/min for 2 weeks), and bilirubin was administered simultaneously in 1 group (3 mg/100 g body weight/48 hr, intraperitoneally). Two weeks after onset of Ang II infusion, systolic blood pressure significantly increased from 134 +/- 4 to 198 +/- 7 mm Hg (P < 0.05) in the Ang II group and from 128 +/- 8 to 209 +/- 9 mm Hg (P < 0.05) in the Ang II + bilirubin group. Relative to the Ang II group, treatment with bilirubin did not alter body weight, food intake, water intake or urine output. However, urinary protein excretion was significantly lower in the Ang II + bilirubin group (32.9 +/- 9.7 mg/d versus 81.4 +/- 22.8 mg/d, P < 0.05). The authors conclude that exogenous bilirubin exerts renoprotective effects in Ang II-dependent hypertension.
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PMID:Bilirubin exerts renoprotective effects in angiotensin II-hypertension. 2058 79

The lungs are a major target for various inflammatory, oxidative, carcinogenic or infectious stressors, which result in a range of lung diseases. Induction of heme oxygenase-1 (HO-1) during acute and chronic lung processes is a crucial defense mechanism. HO-1 catalyzes the degradation of free cellular heme to iron, carbon monoxide (CO) and biliverdin which is eventually converted to bilirubin by biliverdin reductase. In addition to the degradation of free heme, a pro-oxidant, HO-1 exerts anti-oxidant, anti-inflammatory and anti-apoptotic properties via its reaction products. This review summarizes the regulation and protective roles of HO-1 and its reaction products in several in vitro and in vivo lung disease models, including acute lung injury, ischemia-reperfusion (IR)-induced lung injury, cigarette smoke and chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), lung cancer and asthma. The therapeutic applications of HO-1 in the lung as well as potential complications of excessive HO-1 induction are also covered. In summary, the HO-1 system is a powerful endogenous defense strategy with immense therapeutic potential against a range of lung diseases if optimal levels and tissue targeting can be achieved.
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PMID:Heme oxygenase-1 in lung disease. 2070 48

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

Biliverdin reductase A (BLVRA) is a powerful intracellular antioxidant enzyme and an antagonist to insulin-mediated glucose uptake by the cells. Increased oxidative stress and insulin-resistance (IR) are associated with increased risk for hypertension. Therefore, we hypothesized that BLVRA might be attributable to the variation of susceptibility to essential hypertension, and investigated single nucleotide polymorphism (SNP) rs699512 (Thr3Ala), the only common non-synonymous SNP within BLVRA, in population-based samples of 999 Kazak herdsmen from the villages in Xinjiang, China. The minor allele of SNP rs699512 reduced the risk of essential hypertension (age- and gender-adjusted odds ratio 0.76; 95% confidence interval 0.61-0.94; p = 0.010). Single nucleotide polymorphism rs699512 showed association with both systolic and diastolic blood pressures: the minor allele homozygous carriers had lowest systolic and diastolic blood pressures (139.6 mmHg, 89.6mmHg), followed by heterozygous carriers (145.3 mmHg, 92.3 mmHg), and then major allele homozygous carriers (150.3 mmHg, 95.1 mmHg) (p = 0.005 and 0.009, respectively). These findings provide the first genetic evidence for the role of BLVRA on the susceptibility to human essential hypertension and blood pressure.
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PMID:Association of a BLVRA common polymorphism with essential hypertension and blood pressure in Kazaks. 2172 74

Heme oxygenase (HO) is the rate-limiting enzyme in the metabolism of heme-releasing bioactive molecules carbon monoxide (CO), biliverdin, and iron, each with beneficial cardiovascular actions. Biliverdin is rapidly reduced to bilirubin, a potent antioxidant, by the enzyme biliverdin reductase, and iron is rapidly sequestered by ferritin in the cell. Several studies have demonstrated that HO-1 induction can attenuate the development of hypertension as well as lower blood pressure in established hypertension in both genetic and experimental models. HO-1 induction can also reduce target organ injury and can be beneficial in cardiovascular diseases, such as heart attack and stroke. Recent studies have also identified a beneficial role for HO-1 in the regulation of body weight and metabolism in diabetes and obesity. Chronic HO-1 induction lowers body weight and corrects hyperglycemia and hyperinsulinemia. Chronic HO-1 induction also modifies the phenotype of adipocytes in obesity from one of large, cytokine producing to smaller, adiponectin producing. Finally, chronic induction of HO-1 increases oxygen consumption, CO(2), and heat production and activity in obese mice. This review will discuss the current understanding of the actions of the HO system to lower blood pressure and body weight and how HO or its metabolites may be ideal candidates for the development of drugs that can both reduce blood pressure and lower body weight.
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PMID:Heme oxygenase, a novel target for the treatment of hypertension and obesity? 2207 Nov 58

Bilirubin belongs to a phylogenetically old superfamily of tetrapyrrolic compounds, which have multiple biological functions. Although for decades bilirubin was believed to be only a waste product of the heme catabolic pathway at best, and a potentially toxic compound at worst; recent data has convincingly demonstrated that mildly elevated serum bilirubin levels are strongly associated with a lower prevalence of oxidative stress-mediated diseases. Indeed, serum bilirubin has been consistently shown to be negatively correlated to cardiovascular diseases (CVD), as well as to CVD-related diseases and risk factors such as arterial hypertension, diabetes mellitus, metabolic syndrome, and obesity. In addition, the clinical data are strongly supported by evidence arising from both in vitro and in vivo experimental studies. This data not only shows the protective effects of bilirubin per se; but additionally, of other products of the heme catabolic pathway such as biliverdin and carbon monoxide, as well as its key enzymes (heme oxygenase and biliverdin reductase); thus, further underlining the biological impacts of this pathway. In this review, detailed information on the experimental and clinical evidence between the heme catabolic pathway and CVD, and those related diseases such as diabetes, metabolic syndrome, and obesity is provided. All of these pathological conditions represent an important threat to human civilization, being the major killers in developed countries, with a steadily increasing prevalence. Thus, it is extremely important to search for novel markers of these diseases, as well as for novel therapeutic modalities to reverse this unfavorable situation. The heme catabolic pathway seems to fulfill the criteria for both diagnostic purposes as well as for potential therapeutical interventions.
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PMID:The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. 2249 81

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

Hypoxia-induced inhibition of apoptosis in pulmonary artery endothelial cells (PAECs) has an important role in pulmonary arterial remodeling leading to aggravated hypoxic pulmonary arterial hypertension. However, the mechanisms involved in the hypoxia-induced inhibition of PAEC apoptosis have not been elucidated. e-selectin and biliverdin reductase (BVR) have been reported to contribute to the cascade of apoptosis in several cell lines but not in PAECs. In the present study, we show that the expression of e-selectin and BVR was both up-regulated by hypoxia in PAECs. Moreover, hypoxia attenuated the decreased cell survival and apoptotic protein expression, and increased DNA fragmentation induced by serum deprivation in the PAECs, which was mediated by the e-selectin/BVR pathway. In addition, by examining the mitochondrial membrane potential and mitochondrial membrane proteins (Bcl-2 and BAX), we show that the mitochondrial-dependent apoptosis pathway was necessary for the e-selectin/BVR pathway inducing the anti-apoptotic effect of hypoxia in PAECs. Taken all together, our data show that the e-selectin/BVR pathway participates in the inhibitory process of hypoxia in PAEC apoptosis which is mediated by the mitochondrial-dependent apoptosis pathway.
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PMID:Hypoxia inhibits pulmonary artery endothelial cell apoptosis via the e-selectin/biliverdin reductase pathway. 2703 11


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