Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47phox with gp91phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168+/-5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159+/-5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.
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PMID:Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. 1634 66

Superoxide anion (O2*-) is increased throughout the arterial wall in atherosclerosis. The oxidative stress contributes to lesion formation and vascular dysfunction. In the present study, we tested the hypothesis that NAD(P)H oxidase-derived O2*- is increased in nodose sensory ganglia and sympathetic ganglia of apolipoprotein E deficient (apoE-/-) mice, an established animal model of atherosclerosis. O2*- measured ex vivo by L-012-enhanced chemiluminescence was increased by 79+/-17% in whole sympathetic ganglia from apoE-/- mice (n=5) compared with sympathetic ganglia from control mice (n=5) (P<0.05). In contrast, O2*- was not elevated in nodose ganglia from apoE-/- mice. Dihydroethidium staining confirmed the selective increase in O2*- in sympathetic ganglia of apoE-/- mice, and revealed the contribution of both neurons and non-neuronal cells to the O2*- generation. We investigated the enzymatic source of increased O2*- in sympathetic ganglia of apoE-/- mice. The mRNA expression of gp91phox, p22phox, p67phox, and p47phox subunits of NAD(P)H oxidase measured by real time RT-PCR was increased approximately 3-4 fold in sympathetic ganglia of apoE-/- mice (n=5) compared with control ganglia (n=5). NADPH oxidase activity measured by lucigenin chemiluminescence was increased by 68+/-12% in homogenates of sympathetic ganglia from apoE-/- mice (n=7) compared with control ganglia (n=7) (P<0.05). The results identify sympathetic ganglia as a novel site of oxidative stress in atherosclerosis, and suggest that upregulation of NAD(P)H oxidase is the source of increased O2*- generation. We speculate that oxidative stress in sympathetic ganglia may contribute to impaired baroreflex control of sympathetic nerve activity.
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PMID:NAD(P)H oxidase-induced oxidative stress in sympathetic ganglia of apolipoprotein E deficient mice. 1658 25

To characterize novel signaling pathways that underlie NAD(P)H oxidase-mediated signaling in atherosclerosis, we first examined differences in thrombin-induced gene expression between wild-type and p47phox(-/-) (NAD[P]H oxidase-deficient) VSMC. Of the 9000 genes analyzed by cDNA microarray method at the G1/S transition point, 76 genes were similarly and significantly modulated in both the cell types, whereas another 22 genes that encompass various functional groups were regulated in NAD(P)H oxidase-dependent manner. Among these 22 genes, thrombin-induced NAD(P)H oxidase-mediated regulation of Klf15, Igbp1, Ak4, Adamts5, Ech1, Serp1, Sec61a2, Aox1, Aoh1, Fxyd5, Rai14, and Serpinh1 was shown for the first time in VSMC. The role of NAD(P)H oxidase in the regulation of a subset of these genes (CD44, BMP4, Id1, and Id3) was confirmed using modulators of reactive oxygen species (ROS) generation, a ROS scavenger and in gain-of-function experiments. We then characterized regulation of these genes in restenosis and atherosclerosis. In both apoE(-/-) mice and in a mouse vascular injury model, these genes are regulated in NAD(P)H oxidase-dependent manner during vascular lesion formation. Based on these findings, we propose that NAD(P)H oxidase-dependent gene expression in general, and the CD44 and BMP4-Id signaling pathway in particular, is important in restenosis and atherosclerosis.
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PMID:Thrombin and NAD(P)H oxidase-mediated regulation of CD44 and BMP4-Id pathway in VSMC, restenosis, and atherosclerosis. 1660 Dec 25

Hyperhomocysteinaemia is an independent risk factor for cardiovascular diseases due to atherosclerosis. The development of atherosclerosis involves reactive oxygen species-induced oxidative stress in vascular cells. Our previous study [Wang and O (2001) Biochem. J. 357, 233-240] demonstrated that Hcy (homocysteine) treatment caused a significant elevation of intracellular superoxide anion, leading to increased expression of chemokine receptor in monocytes. NADPH oxidase is primarily responsible for superoxide anion production in monocytes. In the present study, we investigated the molecular mechanism of Hcy-induced superoxide anion production in monocytes. Hcy treatment (20-100 microM) caused an activation of NADPH oxidase and an increase in the superoxide anion level in monocytes (THP-1, a human monocytic cell line). Transfection of cells with p47phox siRNA (small interfering RNA) abolished Hcy-induced superoxide anion production, indicating the involvement of NADPH oxidase. Hcy treatment resulted in phosphorylation and subsequently membrane translocation of p47phox and p67phox subunits leading to NADPH oxidase activation. Pretreatment of cells with PKC (protein kinase C) inhibitors Ro-32-0432 (bisindolylmaleimide XI hydrochloride) (selective for PKCalpha, PKCbeta and PKCgamma) abolished Hcy-induced phosphorylation of p47phox and p67phox subunits in monocytes. Transfection of cells with antisense PKCbeta oligonucleotide, but not antisense PKCalpha oligonucleotide, completely blocked Hcy-induced phosphorylation of p47phox and p67phox subunits as well as superoxide anion production. Pretreatment of cells with LY333531, a PKCbeta inhibitor, abolished Hcy-induced superoxide anion production. Taken together, these results indicate that Hcy-stimulated superoxide anion production in monocytes is regulated through PKC-dependent phosphorylation of p47phox and p67phox subunits of NADPH oxidase. Increased superoxide anion production via NADPH oxidase may play an important role in Hcy-induced inflammatory response during atherogenesis.
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PMID:Homocysteine stimulates phosphorylation of NADPH oxidase p47phox and p67phox subunits in monocytes via protein kinase Cbeta activation. 1662 5

Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair as well as in the various pathophysiologies such as ischemic heart and limb diseases and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H(2)O(2) function as signaling molecules in many aspects of growth factor-mediated responses including angiogenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor and stimulates proliferation, migration, and tube formation of endothelial cells (ECs) primarily through the VEGF receptor type2 (VEGR2, KDR/Flk1). VEGF binding initiates autophosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt, and eNOS in ECs, thereby stimulating angiogenesis. The major source of ROS in EC is a NADPH oxidase which consists of Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1. ROS derived from this enzyme stimulate diverse redox signaling pathways leading to angiogenesis-related gene induction as well as EC migration and proliferation, which may contribute to postnatal angiogenesis in vivo. The aim of this review is to provide an overview of the recent progress on the emerging area of the role of ROS derived from NADPH oxidase and redox signaling in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for treatment of angiogenesis-dependent cardiovascular diseases and for promoting angiogenesis in ischemic limb and heart diseases.
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PMID:Redox signaling in angiogenesis: role of NADPH oxidase. 1678 92

Atherosclerosis is an inflammatory disease, occurring preferentially in branched or curved arterial regions exposed to disturbed flow conditions including oscillatory shear stress (OS). In contrast, straight portions exposed to undisturbed laminar shear stress (LS) are relatively lesion free. The opposite effects of atheroprotective LS and proatherogenic OS are likely to be determined by differential expression of genes and proteins, including redox regulating factors. OS induces inflammation via mechanisms involving increased reactive oxygen species (ROS) production from the NADPH oxidases. Through a transcript profiling study and subsequent verification and functional studies, the authors discovered that OS induces inflammation by producing bone morphogenic protein 4 (BMP4) in endothelial cells. BMP4 stimulates expression and activity of NADPH oxidase requiring p47phox and Nox-1 in an autocrine-like manner. The NADPH oxidase activation by BMP4 then leads to ROS production, NF-kappaB activation, intercellular adhesion molecule 1 (ICAM-1) expression, and subsequent increased monocyte adhesivity of endothelial cells. It is proposed that endothelial NADPH oxidases play a critical role in disturbed flow- and BMP4-dependent inflammation, which is the critical early atherogenic response occurring in atheroprone areas. This emerging field of shear stress, BMP4, NADPH oxidases, inflammation, and atherosclerosis is reviewed.
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PMID:Role of NADPH oxidases in disturbed flow- and BMP4- induced inflammation and atherosclerosis. 1698 15

Angiogenesis is a key process involved in normal development and wound repair, as well as ischemic heart and limb diseases, and atherosclerosis. Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, stimulates proliferation, migration, and tube formation of endothelial cells (ECs), primarily through the VEGF receptor type2 (VEGFR2). Reactive oxygen species (ROS) function as signaling molecules to mediate biological responses. In ECs, NADPH oxidase is one of the major sources of ROS and consists of catalytic subunits (Nox1, Nox2, and Nox4), p22phox, p47phox, p67phox, and the small GTPase Rac1. VEGF stimulates ROS production via activation of gp91phox (Nox2)-based NADPH oxidase, and ROS are involved in VEGFR2-mediated signaling linked to EC migration and proliferation. Moreover, ROS derived from NADPH oxidase are involved in postnatal angiogenesis. Localizing NADPH oxidase and its regulators at the specific subcellular compartment is an important mechanism for activating specific redox signaling events. This review focuses on a role of NADPH oxidase-derived ROS in angiogenesis and critical regulators involved in generation of spatially and temporally restricted ROS-dependent VEGF signaling at leading edge, focal adhesions/complexes, caveolae/lipid rafts, and cell-cell junctions in ECs. Understanding these mechanisms should facilitate the development of new therapeutic strategies to modulate new blood vessel formation.
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PMID:VEGF signaling through NADPH oxidase-derived ROS. 1751 88

Reactive oxygen species generated by NADPH oxidase enhance aortic vascular smooth muscle cell proliferation and migration which play an important role in the pathophysiology of atherosclerosis. We investigated the role of NADPH oxidase in the cellular cholesterol metabolism in vascular smooth muscle cells using p47phox-deficient cells. Wild-type and p47phox knockout vascular smooth muscle cells were loaded with cholesterol for 72 h by using 10 mg/L cholesterol:methyl-beta-cyclodextrin complexes and then incubated with or without 0.3 mg/L thrombin for 10 min. Foam cell formation was determined by accumulation of intracellular cholesterol, oil Red O-stained lipid droplets. After cholesterol loading, cellular lipid droplets raised sharply, cellular cholesterol increased from (31.4+/-2.0) to (61.0+/-2.1) mg/g protein (P<0.05) in wild-type cells, and from (29.8+/-2.5) to (51.3+/-3.1) mg/g protein (P<0.05) in p47phox deficient cells, but the difference between the two cell types was not significant. Immunostaining showed decreased levels of smooth muscle alpha-actin and increased levels of macrophage marker Mac-2 in both wild-type and p47phox deficient vascular smooth muscle cells. One of the macrophage-related inflammation genes, monocyte chemoattractant protein-1 (MCP-1) expression did not change in both two cell types detected by immunostaining. Although additional incubating with thrombin, another macrophage-related inflammation gene, vascular cell adhesion molecule-1 (VCAM-1) expression was similar in all groups analyzed by real-time RT-PCR. However, the expression of ATP-binding cassette transporter A1 (ABCA1), acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), the key proteins in cellular cholesterol metabolism, were similarly increased (P<0.05) in both two cell types as determined by quantitative real-time RT-PCR and Western blot, and it was not related to the state of oxidative stress. Interestingly, the expression of adipophilin, the lipid droplet related protein, had the similar results with ABCA1 and ACAT1, but, in wild-type cells, its expression also increased merely incubating with thrombin as determined by quantitative real-time RT-PCR. Together, these results suggest that p47phox-dependent NADPH oxidase is not involved in transdifferentitation of vascular smooth muscle cells into macrophage-like state after cholesterol loading. Deleting p47phox gene does not affect the cellular cholesterol metabolism in vascular smooth muscle cells.
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PMID:[NADPH oxidase activity does not affect cellular cholesterol loading in vascular smooth muscle cells]. 1869 Mar 94

Excess food intake leads to obesity and diabetes, both of which are well-known independent risk factors for atherosclerosis, and both of which are growing epidemics in an aging population. We hypothesized that aging enhances the metabolic and vascular effects of high fat diet (HFD) and therefore examined the effect of age on atherosclerosis and insulin resistance in lipoprotein receptor knockout (LDLR(-/-)) mice. We found that 12-month-old (middle-aged) LDLR(-/-) mice developed substantially worse metabolic syndrome, diabetes, and atherosclerosis than 3-month-old (young) LDLR(-/-) mice when both were fed HFD for 3 months, despite similar elevations in total cholesterol levels. Microarray analyses were performed to analyze the mechanism responsible for the marked acceleration of atherosclerosis in middle-aged mice. Chow-fed middle-aged mice had greater aortic expression of multiple antioxidant genes than chow-fed young mice, including glutathione peroxidase-1 and -4, catalase, superoxide dismutase-2, and uncoupling protein-2. Aortic expression of these enzymes markedly increased in young mice fed HFD but decreased or only modestly increased in middle-aged mice fed HFD, despite the fact that systemic oxidative stress and vascular reactive oxygen species generation, measured by plasma F2alpha isoprostane concentration (systemic) and dihydroethidium conversion and p47phox expression (vascular), were greater in middle-aged mice fed HFD. Thus, the mechanism for the accelerated vascular injury in older LDLR(-/-) mice was likely the profound inability to mount an antioxidant response. This effect was related to a decrease in vascular expression of 2 key transcriptional pathways regulating the antioxidant response, DJ-1 and forkhead box, subgroup O family (FOXOs). Treatment of middle-aged mice fed HFD with the antioxidant apocynin attenuated atherosclerosis, whereas treatment with the insulin sensitizer rosiglitazone attenuated both metabolic syndrome and atherosclerosis. Both treatments decreased oxidative stress. A novel effect of rosiglitazone was to increase expression of Nrf2 (nuclear factor [erythroid-derived 2]-like 2), a downstream target of DJ-1 contributing to enhanced expression of vascular antioxidant enzymes. This investigation underscores the role of oxidative stress when multiple atherosclerotic risk factors, particularly aging, converge on the vessel wall and emphasizes the need to develop effective strategies to inhibit oxidative stress to protect aging vasculature.
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PMID:Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. 1926 38

Xyloketal B is a novel marine compound with unique chemical structure isolated from mangrove fungus Xylaria sp. (no. 2508). Pretreatment with xyloketal B (0.63-40 microM) significantly improved oxLDL (150 microg/ml)-induced injury in human umbilical vein endothelial cells (HUVECs) without either toxic or proliferative effects. Xyloketal B concentration-dependently attenuated oxLDL-induced ROS generation, peroxynitrite formation and decrease of Bcl-2 expression. In addition, xyloketal B significantly inhibited NADPH oxidase activity, as well as mRNA expression of gp91phox and p47phox. Furthermore, xyloketal B alone augmented the production of nitric oxide (NO). Collectively, these data indicate that xyloketal B protects against oxLDL-induced endothelial oxidative injury probably through inhibiting NADPH oxidase-derived ROS generation, promoting NO production and restoring Bcl-2 expression, making it a promising compound for further evaluation in the treatment of atherosclerosis.
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PMID:A novel marine compound xyloketal B protects against oxidized LDL-induced cell injury in vitro. 1948 Oct 65


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