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)

Nitric oxide (NO) induced by bacterial lipopolysaccharide (LPS) plays a critical role in various patho-physiological implications, such as atherosclerosis, vasculitis and septic shock. In addition, cAMP-responsive element binding protein (CREB), an important transcription factor for cell differentiation, has been shown to be involved in atherosclerogenesis in VSMCs. Here we investigated the possibility whether LPS-induced NO signaling led to phosphorylation of cAMP-responsive element binding protein on Serine-133 (CREBSer-133) in cultured vascular smooth muscle cells (VSMCs) from rats. Addition of LPS (1-10 microg/ml) for 48 hours increased not only the production NO, but also the phosphorylation of CREBSer-133. The use of NOS inhibitor (100-500 microM L-NAME) blocked the magnitudes of both LPS-induced NO production and CREBSer-133 phosphorylation. In addition, either a guanylyl cyclase (GC) inhibitor (30 microM ODQ) or a cGMP-dependent protein kinase (PKG) inhibitor (20 microM (Rp)-8-pCPT-cGMPs) significantly attenuated the magnitudes of LPS-induced CREBSer-133 phosphorylation, suggesting the involvement of NO-GC-PKG signaling. Thus, the present study suggests that NO-mediated signaling activated by bacterial LPS, at least in part, enhance CREBSer-133 phosphorylation in cultured VSMCs. The findings here may provide not only signaling pathway involved in VSMC differentiation during inflammatory response, but also new insight into possible therapeutic intervention.
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PMID:Enhancement of CREBSerine-133 phosphorylation through nitric oxide-mediated signaling induced by bacterial lipopolysaccharide in vascular smooth muscle cells from rats. 1281 20

Hyperlipidemia, a condition normally observed in cholestatic liver disease, is also a risk factor for the development of atherosclerosis. The relationship between the elevation of lipoproteins in cholestatic liver diseases and atherosclerosis formation has not been elucidated. In this study, we propose that the impairment of endothelium-dependent relaxation (EDR) of blood vessels in cholestatic liver diseases may lead to the development of atherosclerosis. Using bile duct ligation (BDL) in rats as a model, we examined the liver function, serum lipid profile, EDR and morphologic change of the aorta from both sham operated and BDL rats. Significant increases in liver and spleen weights, serum alanine transaminase (ALT) and aspartate transaminase (AST) activities and the bilirubin level were observed in BDL rats. Upon bile duct ligation, the total and low-density lipoprotein cholesterol levels were increased but the high-density lipoprotein cholesterol and triglyceride levels were reduced. Less contractility and lowered response to acetylcholine-induced relaxation were found in aorta segments. In addition, the acetylcholine-induced relaxation was blocked by both L-NAME and 15 mM KCl. Our results suggest that both nitric oxide and endothelium-derived hyperpolarizing factor are important elements for the impairment of the EDR in BDL rats. In addition, a mild atrophy of the media of the aorta was detected in BDL rats. We conclude that the alterations of lipid profile and the mild atrophy of the media may lead to the impairment of EDR in the aorta in BDL rats, and these factors may potentiate the development of atherosclerosis.
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PMID:Change in lipid profile and impairment of endothelium-dependent relaxation of blood vessels in rats after bile duct ligation. 1285 Feb 41

Many harmful effects of nitric oxide are caused by the reaction of NO with superoxide anion. The present study was carried out to find out the concomitant production of superoxide and to investigate a suitable inhibitor of NO, which is produced by iNOS. THP-1 cells were differentiated into macrophages by PMA and cytokine. Addition of L-NAME showed decrement in superoxide production. Addition of apocynin, aminoguanidine or ONO 1714 brought about a significant reduction in superoxide production. The expressions of p67 and p47(phox) were reduced by the addition of apocynin, aminoguanidine or ONO 1714 whereas xanthine oxidase and cyclooxygenase did not have a major role in superoxide production. The results of the present study show that iNOS and NADPH oxidase play an important role in superoxide release. It suggests that addition of iNOS inhibitor together with apocynin may be more effective in case of therapeutic application in disease conditions like atherosclerosis.
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PMID:Concomitant production of nitric oxide and superoxide in human macrophages. 1452 19

Endothelial injuries induced by different stimuli lead to proliferation of intimal vascular smooth muscle cells with formation of neointima. In this functional study, we evaluated the reactivity to contracting and vasorelaxing agents in Wistar rat carotid artery at different times (1, 7, 14, 21 and 28 days) after endothelial denudation with angioplastic balloon technique. Injured (IC) and uninjured carotid artery rings (UC) were placed in an isolated organ bath for isometric force displacement. IC collected at 1, 7, 14, 21 and 28 days showed a reduction in contraction to phenylephrine (0.3 microM), angiotensin II (0.1 microM), U46619 (0.1 microM), KCl (60 mM) and A23187 (1microM) at any experimental time compared to rings obtained from UC. The evaluation of endothelial-derived relaxing or hyperpolarizing factor (EDRF or EDHF), induced by acetylcholine (0.001-1 microM) in presence of indomethacin (10 microM) or indomethacin and Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) (10 and 100 microM, respectively), was carried out at 14, 21 and 28 days. The EDRF-induced relaxation was significantly (P < 0.0001) reduced at 14 days and it improved through out the observation time, indeed at 28 days it was indistinguishable from UC relaxation curve. In contrast, the EDHF-induced relaxation was significantly (P < 0.0001) reduced at all experimental time. A significant reduction in nitric oxide-induced relaxation, sodium nitroprusside (0.001-10 microM), was observed at 7, 14 and 21 days, but not at 28 days. The relaxation induced by diazoxide (3-300 microM), an opener of KATP channels, was significantly reduced only at 7 days but not at 14, 21 and 28 days. Western blot analysis of myosin heavy chain revealed that up to 28 days the re-differentiation (maturity state) of smooth muscle cells was not yet reached. In conclusion, our data showed that hyporeactivity to contracting and relaxing agents in endothelial denuded carotid of rats could be linked to a multifactorial condition in which reduction of receptors and alterations in post-receptor transductions in neointima may produce modification of protein expression and/or variation in ion flux where calcium could have a pivotal role.
Atherosclerosis 2003 Dec
PMID:Time course of vascular reactivity to contracting and relaxing agents after endothelial denudation by balloon angioplasty in rat carotid artery. 1464 85

In the present study, we investigated whether low shear (LS, 2 dyn/cm2) favors high glucose (HG, 30 mM) induced nuclear factor kappa B (NF-kappaB) activity by regulating NO release in human aortic endothelial cells (HAEC). The results show that (i) under LS, the NF-kappaB activity of HAEC exposed to HG was significantly higher than HAEC in normal glucose (NG, 5.5mM) (P < 0.05). In contrast, under HS, the activation of NF-kappaB in HAEC exposed to HG showed no significant difference compared to that of NG. (ii) The NF-kappaB activity induced by HG is suppressed by high shear (HS) in the absence of a NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME) but restored in its presence, while LS + HG induced NF-kappaB activity remains the same in the presence or absence of L-NAME. (iii) Endothelial nitric oxide synthase (eNOS) protein expression and quantitative detection of NO indicated that high shear stress significantly induced higher eNOS expression and NO production compared to low shear stress condition. Collectively, these data suggest that HS exerts a protective effect on HG induced NF-kappaB activity through NO mediated signaling. LS, on the other hand, may down-regulate eNOS expression resulting in reduced NO release, and thereby maintain high glucose induced NF-kappaB DNA-binding activity. These observations explain, in part, the mechanism by means of which hyperglycemia accelerates the focal development of atherosclerotic lesions in low shear (lesion prone) areas of the arterial tree.
Atherosclerosis 2003 Dec
PMID:High glucose induced NF-kappaB DNA-binding activity in HAEC is maintained under low shear stress but inhibited under high shear stress: role of nitric oxide. 1464 91

Hypertension is a major risk factor for atherosclerosis and the genesis of cardiovascular and cerebrovascular diseases. Therefore, the protection of atherosclerosis progression is one of the purpose of an anti-hypertensive treatment in vascular system. Nitric oxide (NO)-releasing drugs have been reported to have an inhibitory effect on shear stress-induced extracellular signal-regulated kinase (ERK) activation in endothelial cells. For further understanding of the effects of these drugs, the present study focused on the effects on intracellular signal transduction and cell proliferation in cultured human aortic smooth muscle cells (HASMC) under high atmospheric pressure. Three hours of 160-mmHg atmospheric pressure resulted in an approximately 380% increase in cell proliferation compared to non-pressurized controls. Nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylaminoproxy)-3-nitroxy-2H-1-benzopyran) (10(-6)M) demonstrated approximately 40% reduction in cell proliferation compared to that shown by pressurized HASMC as a vehicle control. Three hours of 160-mmHg atmospheric pressure resulted in a 25% increase in the amount of activated ERKs. Nipradilol (10(-6)M) demonstrated approximately a 26% reduction in the amount of activated ERKs. NO(x) concentration under the presence of nipradilol (10microM) with HASMC resulted in a 7.2microM of NO production and was 2.4-fold more than that from no dug control (3.0microM). An administration of L-NAME (10(-4)M) supplemented with Nipradilol (10(-6)M) did not show any significant effect on cell proliferation. From these observations, we concluded that nipradilol has an anti-proliferative effect on HASMC under high atmospheric pressure. Nipradilol may act as a nitric oxide inducer from HASMC and suspected to work as a supplement to mitigate the impaired endothelial cell function caused by hypertension.
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PMID:Nipradilol inhibits atmospheric pressure-induced cell proliferation in human aortic smooth muscle cells. 1472 16

Reactive oxygen species (ROS) including nitric oxide (NO) and superoxide anion (O(2)(-)) are associated with cell migration, proliferation and many growth-related diseases. The objective of this study was to determine whether there was a reciprocal relationship between rat coronary microvascular endothelial cell (CMEC) growth and activity/expressions (mRNA and protein) of endothelial NO synthase (eNOS) and NAD(P)H oxidase enzymes. Proliferating namely, 50% confluent CMEC possessed approximately threefold increased activity and expression of both enzymes compared to 100% confluent cells. Treatment of CMEC with an inhibitor of eNOS (L-NAME, 100 microM) increased cell proliferation as assessed via three independent methods, i.e. cell counting, determination of total cellular protein levels and [(3)H]-thymidine incorporation. Similarly, treatment of CMEC with pyrogallol (0.3-3 mM), a superoxide anion (O(2)(-)) generator, also increased CMEC growth while spermine NONOate (SpNO), a NO donor, significantly reduced cell growth. Co-incubation of CMEC with a cell permeable superoxide dismutase mimetic (Mn-III-tetrakis-4-benzoic acid-porphyrin; MnTBAP) plus either pyrogallol or NO did not alter cell number and DNA synthesis thereby dismissing the involvement of peroxynitrite (OONO(-)) in CMEC proliferation. Specific inhibitors of NAD(P)H oxidase but not other ROS-generating enzymes including cyclooxygenase and xanthine oxidase, attenuated cell growth. Transfection of CMEC with antisense p22-phox cDNA, a membrane-bound component of NAD(P)H oxidase, resulted in substantial reduction in [(3)H]-thymidine incorporation, total cellular protein levels and expression of p22-phox protein. These data demonstrate a cross-talk between CMEC growth and eNOS and NAD(P)H oxidase enzyme activity and expression, thus suggesting that the regulation of these enzymes may be critical in preventing the initiation and/or progression of coronary atherosclerosis.
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PMID:Nitric oxide synthase and NAD(P)H oxidase modulate coronary endothelial cell growth. 1487 55

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.
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PMID:Anti-lipid deposition effect of HMG-CoA reductase inhibitor, pitavastatin, in a rat model of hypertension and hypercholesterolemia. 1496 17

Endothelial cell dysfunction (ECD) is emerging as a common denominator for diverse cardiovascular abnormalities associated with inhibition of endothelial nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine (ADMA), a potent eNOS inhibitor, are common in renal failure and may contribute to ECD. Through DNA microarray screening of genes modulated in human umbilical vein endothelial cells (HUVEC) by N(G)-nitro-l-arginine methyl ester (l-NAME), we found a 1.8-fold increase in low-density lipoprotein receptor-1 (LOX-1) expression. LOX-1 is a major endothelial receptor for oxidized low-density lipoproteins (OxLDL) and is assumed to play a role in the initiation and progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA and protein level by quantitative RT-PCR and Western blot analysis. Increased expression of LOX-1 was associated with the accumulation of DiI-labeled OxLDL (DiI-OxLDL) in ADMA- and l-NAME-pretreated HUVEC. To evaluate the contribution of LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC, we used the competitive receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was associated with an approximately two- to threefold inhibition of DiI-OxLDL uptake in l-NAME- or ADMA-treated HUVEC. In conclusion, ADMA- or l-NAME-induced NO deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC, which in turn results in the accumulation of OxLDL. Competition with LOX-1-soluble extracellular domain reduces OxLDL accumulation. In summary, elevated ADMA levels, i.e., in patients with renal failure, may be responsible for endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus contributing to endothelial lipidosis and dysfunction.
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PMID:Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency. 1501 Mar 59

This is an overview of recent findings, mainly from our laboratory, describing the cardiovascular functional phenotypes and pharmacological responses in mice genetically deficient in apolipoprotein E (apoE-KO). ApoE-KO mice are hyperlipidemic and spontaneously develop atherosclerosis. We have detected several new cardiovascular functional phenotypes in apoE-KO mice: hyperglycemia, age-dependent aortic stiffening, cardiac hypertrophy and increased cardiac output. Angiotensin II (Ang II) promoted vascular inflammation and atherosclerosis, increased vascular stiffness, and induced abdominal aortic aneurysm (AAA) in apoE-KO mice, in which activation of NF-kappaB mediated pro-inflammatory genes plays an important role. Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly inhibited NO-mediated vascular responses and accelerated atherosclerosis in apoE-KO mice, supporting a protective role of NO against atherosclerosis. Estrogen attenuated atherosclerosis in apoE-KO mice, even in those with atherosclerosis being accelerated by Ang II, hyperglycemia, or L-NAME, demonstrating an anti-atherosclerotic effect of estrogen. Simvastatin paradoxically increased lipid and atherosclerosis in apoE-KO mice, but it decreased lipid and atherosclerosis in LDLR-KO mice, indicating that anti-atherosclerotic effect of simvastatin requires the presence of an intact apoE.
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PMID:Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice. 1563 8


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