Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We investigated the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) on the inhibitory effects of an angiotensin II type-1 receptor (AT1) blocker on atherosclerosis and explored cellular mechanisms. We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition. Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration; however, both drugs decreased plaque area and lipid deposition after 10 weeks. We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day, respectively. At these doses, neither drug had an effect on atherosclerotic lesions. When both drugs were combined at these doses, a significant reduction in atherosclerotic lesions was observed. Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits p22phox and p47phox, production of superoxide anion, the expression of monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 expression were observed. These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade, particularly when given concomitantly, blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects.
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PMID:Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. 1545 25

Angiogenesis, a process of new blood vessel growth, contributes to various pathophysiologies such as cancer, diabetic retinopathy and atherosclerosis. Accumulating evidence suggests that cardiovascular diseases are associated with increased oxidative stress in blood vessels. Reactive oxygen species (ROS) such as superoxide and H2O2 cause blood vessels to thicken, produce inflammation in the vessel wall, and thus are regarded as "risk factors" for vascular disease, whereas ROS also act as signaling molecules in many aspects of growth factor-mediated physiological responses. Recent reports suggest that ROS play an important role in angiogenesis; however, its underlying molecular mechanisms remain unknown. Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell (EC) proliferation and migration primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). VEGF binding initiates tyrosine phosphorylation of KDR, which results in activation of downstream signaling enzymes including ERK1/2, Akt and eNOS, which contribute to angiogenic-related responses in EC. Importantly, the major source of ROS in EC is a NAD(P)H oxidase and EC express all the components of phagocytic NAD(P)H oxidase including gp91phox, p22phox, p47phox, p67phox and the small G protein Rac1. We have recently demonstrated that ROS derived from NAD(P)H oxidase are critically important for VEGF signaling in vitro and angiogenesis in vivo. Furthermore, a peptide hormone, angiotensin II, a major stimulus for vascular NAD(P)H oxidase, also plays an important role in angiogenesis. Because EC migration and proliferation are primary features of the process of myocardial angiogenesis, we would like to focus on the recent progress that has been made in the emerging area of NAD(P)H oxidase-derived ROS-dependent signaling in ECs, and discuss the possible roles in angiogenesis. Understanding these mechanisms may provide insight into the components of NAD(P)H oxidase as potential therapeutic targets for treatment of angiogenesis-dependent diseases such as cancer and atherosclerosis and for promoting myocardial angiogenesis in ischemic heart diseases.
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PMID:Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. 1554 38

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Since reactive oxygen species (ROS) induce MMP-2 and angiotensin II (ANG II) enhances NADPH-oxidase-dependent ROS formation, we assessed whether ANG II induces MMP-2 in a NADPH-oxidase-dependent manner. MMP-2 mRNA expression and activity were analyzed in wildtype and p47phox-deficient (p47phox-/-) murine smooth muscle cells (SMC). To address a clinical implication, sections of human atherosclerotic arteries were stained for MMP-2, p47phox, ANG II, AT1-receptor, and alpha-smooth muscle cell actin (alpha-SMC actin). MMP-2 protein expression and activity from these arteries were compared to those without atherosclerosis. ANG II enhances mRNA synthesis and activity of MMP-2 in a p47phox-dependent manner. Immunohistochemical analyses revealed a co-localization of MMP-2 with p47phox, ANG II, AT1-receptor, and alpha-SMC actin. MMP-2 protein expression and gelatinolytic activity are increased in atherosclerotic arteries. Thus, activation of the renin-angiotensin system may contribute to plaque destabilization via ROS-dependent induction of MMP-2.
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PMID:Angiotensin II induces MMP-2 in a p47phox-dependent manner. 1567 Jul 68

The present study explored the possibility that estrogen enhances the inhibitory effect of an angiotensin II type-1 (AT1) receptor blocker (ARB), olmesartan, on atherosclerosis, focusing on oxidative stress using apolipoprotein E knockout mice (ApoEKO). After 6 weeks on a high-cholesterol diet, marked atherosclerotic lesion formation with an increase in oxidative stress, such as superoxide production, NAD(P)H oxidase activity and expression of p47phox mRNA and rac-1 mRNA, were observed in the proximal aorta in both male and female ApoEKO mice, whereas these changes were less marked in female mice. Ovariectomy enhanced these parameters, the changes of which were reversed by 17beta-estradiol (80 microg/kg per day) replacement. Treatment with olmesartan (3 mg/kg per day) significantly inhibited oxidative stress and atherosclerosis, whereas its inhibitory effects were more marked in female than in male or ovariectomized mice. Smaller doses of olmesartan (0.5 mg/kg per day) or 17beta-estradiol (20 microg/kg per day) did not influence atherosclerosis and oxidative stress in ovariectomized mice, whereas co-administration of olmesartan and 17beta-estradiol at these doses attenuated these parameters. An angiotensin-converting enzyme (ACE) inhibitor, temocapril, also inhibited atherosclerotic changes similarly to olmesartan. Moreover, angiotensin II-mediated activation of NAD(P)H oxidase in cultured vascular smooth muscle cells was attenuated by 17beta-estradiol. These results indicate that estrogen and an ARB synergistically attenuate atherosclerosis at least partly via inhibition of oxidative stress.
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PMID:Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. 1572 67

The association between cigarette smoking and atherogenesis is well established. Inflammatory cells may participate in atherogenesis via activation of the NADPH oxidase and the subsequent production of reactive oxygen species (ROS), which exacerbates endothelial injury. However, little is known about the ability of cigarette smoke (CS) to modulate NADPH oxidase protein function. In this study, we investigated the ability of a CS extract derived from a high tar cigarette to alter human neutrophil ROS production and the translocation of two NADPH oxidase proteins, p47phox and p67phox. Phorbol ester-induced intracellular and extracellular production of ROS was reduced following CS treatment as measured by enhanced luminol or isoluminol chemiluminescence, respectively, (luminol AUC was reduced by 59%, p < or =0.0001; isoluminol by 49%, p < or =0.001). The phorbol ester-induced phosphorylation and translocation of p47phox from the cytosol to the membrane was not changed by CS treatment but the translocation of p67phox was reduced. Cigarette smoke treatment alone did not provoke neutrophil ROS production. These findings demonstrate that CS treatment reduced agonist-induced human neutrophil ROS production independent of p47phox phosphorylation and translocation from the cytosol to the membrane. However, this inhibition could be attributed to a reduction in translocation of another cytosolic NADPH oxidase protein, p67phox. Although neutrophil-generated ROS have been implicated in the pathogenesis of atherosclerosis, this does not appear to be the mechanism by which CS induces vascular injury.
Atherosclerosis 2005 Apr
PMID:Inhibition of human neutrophil reactive oxygen species production and p67phox translocation by cigarette smoke extract. 1577 40

Although diabetes is a major risk factor for vascular diseases, e.g., hypertension and atherosclerosis, mechanisms that underlie the "risky" aspects of diabetes remain obscure. The current study is intended to examine the notion that diabetic endothelial dysfunction stems from a heightened state of oxidative stress induced by an imbalance between vascular production and scavenging of reactive oxygen/nitrogen species. Goto-Kakizaki (GK) rats were used as a genetic animal model for non-obese type II diabetes. Nitric oxide (NO) bioavailability and O2- generation in aortic tissues of GK rats were assessed using the Griess reaction and a lucigenin-chemiluminescence-based technique, respectively. Organ chamber-based isometric tension studies revealed that aortas from GK rats had impaired relaxation responses to acetylcholine whereas a rightward shift in the dose-response curve was noticed in the endothelium-independent vasorelaxation exerted by the NO donor sodium nitroprusside. An enhancement in superoxide (O2-) production and a diminuation in NO bioavailability were evident in aortic tissues of GK diabetic rats. Immunoblotting and high-performance liquid chromatography (HPLC)-based techniques revealed, respectively, that the above inverse relationship between O2- and NO was associated with a marked increase in the protein expression of nitric oxide synthase (eNOS) and a decrease in the level of its cofactor tetrahydrobiopterin (BH4) in diabetic aortas. Endothelial denudation by rubbing or the addition of pharmacological inhibitors of eNOS (e.g. N(omega)-nitro-L-arginine methyl ester (L-NAME)), and NAD(P)H oxidase (e.g. diphenyleneiodonium, apocynin) strikingly reduced the diabetes-induced enhancement in vascular O2- production. Aortic contents of key markers of oxidative stress (isoprostane F2alpha III, protein-bound carbonyls, nitrosylated protein) in connection with the protein expression of superoxide generating enzyme NAD(P)H oxidase (e.g. p47phox, pg91phox), a major source of reactive oxygen species in vascular tissue, were elevated as a function of diabetes. In contrast, the process involves in the vascular inactivation of reactive oxygen species exemplified by the activity of CuZnSOD was reduced in this diseased state. Our studies suggest that diabetes produces a cascade of events involving production of reactive oxygen species from the NADPH oxidase leading to oxidation of BH4 and uncoupling of NOS. This promotes the oxidative inactivation of NO with subsequent formation of peroxynitrite. An alteration in the balance of these bioactive radicals in concert with a defect in the antioxidant defense counteracting mechanism may favor a heightened state of oxidative stress. This phenomenon could play a potentially important role in the pathogenesis of diabetic endothelial dysfunction.
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PMID:Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. 1577 79

The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall. Therefore, investigating the effects of these abnormal reactions on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis. Three types of peroxisome proliferator-activated receptors (PPARs): PPARalpha, PPARbeta/delta, and PPARgamma are expressed in endothelial cells. In endothelial cells, the ligands/activators for PPARalpha and PPARgamma increase Cu2+, Zn2+ -superoxide dismutase. In addition, the phorbol myristate acetate (PMA)-stimulated 22 kDa-subunit (p22phox) protein levels and 47 kDa-subunit (p47phox) protein levels in NADPH (superoxide generating enzyme nicotinamide adenine dinucleotide phosphate (reduced form)) oxidase were decreased by treatment with PPARalpha and PPARgamma ligands/activators. Recently, we showed that the CLOCK: BMAL1 heterodimer regulates the PPARalpha gene via promoter of PPARalpha. Moreover, we report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia, in which the former may have caused the latter two conditions. This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function. Here, based on recent studies including our own, we describe the relationships between risk factors for atherosclerosis, especially hyperlipidemia and PPARs and the molecular mechanisms that govern lipid metabolism in the arteries.
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PMID:[Hyperlipidemia and peroxisome proliferator-activated receptor (PPAR)--regulation of the PPARalpha gene by CLOCK: BMAL1]. 1582 32

Vascular NAD(P)H oxidases are multicomponent enzymes found in vascular smooth muscle cells and endothelial cells. Vascular NAD(P)H oxidases are predominant sources of superoxide in the vasculature. Active forms of NAD(P)H oxidases are associated with plasma membrane and consist of at least six components, namely: NOX, p22phox peptides and p47phox, p67phox, p40phox and Rac. Angiotensin II is the most important activator of NAD(P)H oxidases in vasculature. Angiotensin II induces superoxide and superoxide-derived hydrogen peroxide production, which may stimulate many proatherosclerotic processes, including increased expression of adhesion molecules, chemoattractants and activation of transcription factor NF-kappaB. Moreover, reactive oxygen species produced by NAD(P)H oxidases may be involved in endothelial cells apoptosis, oxidation of low density lipoproteins and vascular myocytes hypertrophy and proliferation. Specific inhibitors of NAD(P)H oxidases may be useful experimental tools for atherosclerosis research and may have potential therapeutic significance in the future.
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PMID:[Vascular NAD(P)H oxidases--role in the pathogenesis of atherosclerosis]. 1620 36

To elucidate the molecular mechanisms of the cardioprotective effect of angiotensin-converting enzyme (ACE) inhibitors, we evaluated whether the effect of quinapril involved in bradykinin-endothelial nitric oxide synthase (eNOS) and oxidative stress-lectin-like oxidized LDL receptor-1 (LOX-1) pathway. Dahl salt-sensitive hypertensive (DS) rats were fed a diet containing 8% NaCl and treated with one of the following drug combinations for 5 weeks, from 6 weeks of age to left ventricular hypertrophy stage (11 weeks): vehicle; quinapril; quinapril plus the bradykinin B2 receptor antagonist FR172357; the NAD(P)H oxidase inhibitor apocynin; or quinapril plus apocynin. eNOS expression, which was decreased in hypertrophy stage, was significantly increased by quinapril and/or apocynin, but not by quinapril plus FR172357. Upregulated expression of NAD(P)H oxidase p22phox, p47phox, gp91phox and LOX-1 was significantly decreased by quinapril to a similar degree as after treatment with apocynin, but not by quinapril plus FR172357. Quinapril and/or apocynin treatment effectively ameliorated left ventricular weight and vascular changes such as increase in medial thickness and perivascular fibrosis and suppressed expression of transforming growth factor-beta1, type I collagen and fibronectin mRNA, but not that of quinapril plus FR172357. These results suggest that the ACE inhibitor quinapril may have cardioprotective effects in this model of hypertension mediated at least in part through effects on the bradykinin-eNOS and oxidative stress-LOX-1 pathway.
Atherosclerosis 2006 Jul
PMID:Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition. 1621 49

Endothelial dysfunction is characterized by impaired vasodilation, increase of oxidative stress and inflammation. The current study was designed to test the hypothesis that reversal of hypercholesterolemic diet alone does not normalize all the parameters of endothelial dysfunction. After 10 weeks on a high-cholesterol diet, female juvenile pigs were randomized to normal diet (n=5, "Reversals") or continued on the same diet (n=6, "HC") for another 6 weeks. A control group of 11 pigs received a normal diet ("C"). Coronary epicardial and arteriolar endothelial function was tested in vitro. NFkappaB and p47phox expression was analyzed in epicardial arteries and myocardium, respectively. P47phox localization in coronary arteries was demonstrated with immunohistochemistry. Lipid levels normalized in Reversal pigs. Epicardial arteries of Reversals showed a normalized relaxation and NFkappaB expression compared to HC (p<0.05). Small vessel relaxation remained attenuated, and expression of p47phox in myocardial tissue was elevated in Reversals compared to C (p<0.05). Dietary lowering of serum cholesterol and LDL improves vascular function of epicardial arteries but neither of small vessels nor vascular oxidative stress within this time frame. Hence, dietary normalization of serum lipid levels alone may not be synonymous to normalization of the components of endothelial dysfunction.
Atherosclerosis 2006 Oct
PMID:Dietary reversal of experimental hypercholesterolemia improves endothelial dysfunction of epicardial arteries but not of small coronary vessels in pigs. 1634 7


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