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

Heme oxygenase-1 (HO-1) has been demonstrated to exert potent anti-oxidant and anti-inflammatory effects in the context of atherosclerotic vascular disease, and therefore was referred to as a potential vascular protective factor. A (GT)n dinucleotide repeat polymorphism in the HO-1 promoter has been shown to modulate HO-1 gene expression. Short (<25) GT repeats were associated with HO-1 up-regulation, and therefore may influence susceptibility to ischaemic vascular events. We investigated the association of HO-1 repeat length with the risk of cerebrovascular events in a case control study and assessed possible interrelations with vascular risk factors. We determined the number of GT repeats in the HO-1 promoter in 399 patients with ischaemic cerebrovascular events and 398 healthy controls and compared the frequencies of short (<25) repeat (class S) and long (> or =25) repeat (class L) alleles after adjustment for potentially confounding factors. Genotype distributions of S/S, S/L and L/L in patients were 9.8% (n=39), 45.1% (n=180) and 45.1% (n=180), which was similar to the distribution in controls with 11.5% (n=46), 44.5% (n=177) and 44.0% (n=175). In the presence of vascular risk factors, the HO-1 genotype became functionally relevant: in patients without hyperlipidemia the S/S genotype exerted a protective effect on the development of ischaemic cerebrovascular events (OR 0.2; 95% CI 0.1-0.6), while this effect was no longer present in hyperlipidemic patients. Short (<25 GT) repeats in the HO-1 gene promoter confer a reduced risk for cerebrovascular events in individuals with normal plasma lipid levels. This may explain controversial findings in different populations.
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PMID:The effect of a promoter polymorphism in the heme oxygenase-1 gene on the risk of ischaemic cerebrovascular events: the influence of other vascular risk factors. 1514 May 86

Heme oxygenase-1 (HO-1) is a cytoprotective protein whose expression is consistently associated with therapeutic benefits in a number of pathologic conditions such as atherosclerotic vascular disease and inflammation. Although the expression of HO-1 in most tissues is low, a large number of clinical and experimental pharmacologic compounds have been demonstrated to induce HO-1. This induction is suggested to be at least partially responsible for the perceived therapeutic efficacy of these compounds. The increase in HO-1 expression in response to these compounds is the result of a complex regulatory network involving many signaling pathways and transcription factors. Understanding both the pathways by which HO-1 is induced and the mechanism through which the enzyme exerts its beneficial effects may facilitate the development of novel drugs.
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PMID:Pharmacologic induction of heme oxygenase-1. 1782 67

Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, has been shown to play a regulatory role in the expression of plasminogen activator inhibitor-1 (PAI-1), a risk factor for vascular disease. Accordingly, we examined the effect of protoporphyrins, both HO inhibitors and activators, on PAI-1 expression in human vascular smooth muscle cells (VSMCs). Tin-protoporphyrin (SnPP) markedly inhibited the transforming growth factor beta1 (TGFbeta1)-induced expression of PAI-1 protein. Protoporphyrins, whether they are inhibitors or activators of HO, produced a similar inhibitory effect. However, SnPP had no effect on the level of PAI-1 mRNA transcripts. Knockdown of human HO-1 with a specific siRNA did not reduce the PAI-1 protein level in TGFbeta1-treated cells. In addition, the proteasome inhibitor lactacystin reversed the inhibitory effect of SnPP on PAI-1 protein expression. Both cobalt-protoporphyrin (CoPP) and CoCl2 markedly induced HO-1 expression. However, CoPP did not affect PAI-1 gene expression, whereas CoCl2 upregulated PAI-1 mRNA in a dose-dependent manner. Our results demonstrate that protoporphyrins can block the TGFbeta1-mediated induction of PAI-1 protein in VSMCs and that this inhibitory effect is independent of HO activity.
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PMID:Inhibition of plasminogen activator inhibitor-1 expression in vascular smooth muscle cells by protoporphyrins through a heme oxygenase-independent mechanism. 1834 23

Heme oxygenase-1 (HO-1), a ubiquitous inducible stress-response protein, serves a major metabolic function in heme turnover. HO activity cleaves heme to form biliverdin-IXalpha, carbon monoxide (CO), and iron. Genetic experiments have revealed a central role for HO-1 in tissue homeostasis, protection against oxidative stress, and in the pathogenesis of disease. Four decades of research have witnessed not only progress in elucidating the molecular mechanisms underlying the regulation and function of this illustrious enzyme, but also have opened remarkable translational applications for HO-1 and its reaction products. CO, once regarded as a metabolic waste, can act as an endogenous mediator of cellular signaling and vascular function. Exogenous application of CO by inhalation or pharmacologic delivery can confer cytoprotection in preclinical models of lung/vascular injury and disease, based on anti-apoptotic, anti-inflammatory, and anti-proliferative properties. The bile pigments, biliverdin and bilirubin, end products of heme degradation, have also shown potential as therapeutics in vascular disease based on anti-inflammatory and anti-proliferative activities. Further translational and clinical trials research will unveil whether the HO-1 system or any of its reaction products can be successfully applied as molecular medicine in human disease.
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PMID:Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy. 1961 98

Heme-oxygenase-1 (HO-1), an important enzyme involved in vascular disease, transplantation, and inflammation, catalyzes the degradation of heme into carbon monoxide and biliverdin. It has been reported that overexpression of HO-1 inhibits osteoclastogenesis. However, the effect of HO-1 on osteoblast differentiation is still not clear. We here used adenoviral vector expressing recombinant human HO-1 and HO-1 inducer hemin to study the effects of HO-1 in primary cultured osteoblasts. The results showed that induction of HO-1 inhibited the maturation of osteoblasts including mineralized bone nodule formation, alkaline phosphatase activity and decreased mRNA expression of several differentiation markers such as alkaline phosphatase, osteocalcin, and RUNX2. Furthermore, downstream products of HO-1, bilirubin, carbon monoxide, and iron, are involved in the inhibitory action of HO-1. HO-1 can be induced by H(2)O(2), lipopolysaccharide and inflammatory cytokines such as TNF-alpha and IL-1beta in osteoblasts and also in STZ-induced diabetic mice. In addition, endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin-J2 (15d-PGJ2) markedly increased both mRNA and protein levels of HO-1 in osteoblasts via PI3K-Akt and MAPK pathways. Blockade of HO activity by ZnPP IX antagonized the inhibitory action on osteocalcin expression by hemin and 15d-PGJ2. Our results indicate that upregulation of HO-1 inhibits the maturation of osteoblasts and HO-1 may be involved in oxidative- or inflammation-induced bone loss.
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PMID:Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts. 2002 Apr 68

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

Heme oxygenase-1 (HO-1, encoded by the HMOX1 gene) and inducible nitric oxide synthase (iNOS) have been implicated in vascular disease; however the role of these genes remains unclear. Therefore, we studied the mechanism by which iNOS-derived nitric oxide (NO) affects the intimal hyperplasia (IH) formation in relation to HO-1. We show, in a model of balloon injury in rats, that the suppression of vascular smooth muscle cells (VSMC) proliferation by NO required HO-1, while induction of apoptosis of the VSMC by NO does not involve HO-1. To better clarify the molecular mechanism of this finding, we used Hmox1(+/+) and Hmox1(-/-) VSMC exposed to NO. In Hmox1(+/+) VSMC, NO is antiproliferative (up to 34% inhibition) and it is associated to an increase of apoptosis (up to 35%) due to a decrease of X-linked inhibitor of apoptosis protein (XIAP) expression level and to the activation of caspase-3. In the absence of HO-1 (Hmox1(-/-) VSMC) apoptosis was significantly greater (69% p<0.01 vs. Hmox1(+/+) VSMC) demonstrating that HO-1 attenuated the pro-apoptotic effect of NO on VSMC. In the context of IH, the pro-apoptotic effect of NO on VSMC is increased in the absence of HO-1 and exerts therapeutic effects with a significant reduction in IH.
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PMID:Heme oxygenase-1 inhibition prevents intimal hyperplasia enhancing nitric oxide-dependent apoptosis of vascular smooth muscle cells. 2180 7

Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.
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PMID:Heme and FLVCR-related transporter families SLC48 and SLC49. 2350

Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.
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PMID:A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine, Sphingosine-1-Phosphate, and Heme of Human Lung. 2631 40


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