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)

Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.
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PMID:Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure. 1602 19

Pathological hypoxia plays an important role in many diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. The aim of the present study was to examine the effects of different statins on hypoxia-induced endothelial cell signalling. Human umbilical cord vein endothelial cells (HUVEC) were treated with NaCN (CN, 2.5 mmol/l) to simulate a transient hypoxia. The CN-induced increase of endothelial cell numbers was significantly (n = 10, p < 0.01) reduced by the Ca(2+) chelator BAPTA (10 micromol/l), or the reactive oxygen species (ROS) scavenger N-acetylcysteine (ACC, 1 mmol/l), or the NAD(P)H-oxidase inhibitor diphenyleneiodonium (DPI, 5 micromol/l). In detail, cell numbers were (in percentage of control): 163.24 (CN), 90.06 (CN+ACC), 92.06 (CN+DPI). Intracellular-Ca(2+) and -ROS, analysed by fluorescence imaging, were significantly increased by CN. Interestingly, the CN-induced increase of ROS was in part Ca(2+)-dependent, whereas the Ca(2+) increase was not ROS-dependent. Simvastatin (5 micromol/l), fluvastatin (2.5 micromol/l), and cerivastatin (0.1 micromol/l) all reduced CN-induced proliferation, ROS generation and Ca(2+) increase. Cell viability was not reduced by the statins and the antiproliferative effect was completely reversed by mevalonate (500 micromol/l). In conclusion our study demonstrates that statins block hypoxia-associated endothelial proliferation by preventing the increase of Ca(2+) and ROS.
Atherosclerosis 2006 Apr
PMID:Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation. 1611 21

Angiotensin II is involved in the process of atherosclerosis and stimulates superoxide production from cardiovascular cells. We examined the effect of telmisartan, an angiotensin II type 1 receptor blocker, on atherosclerosis. We chronically treated apolipoprotein E-deficient mice with two different doses of telmisartan dissolved in drinking water (0.3 and 3 mg/kg) starting from 4 weeks of age for 12 weeks. Lipid contents were not different in both telmisartan-treated groups compared with control group. Systolic blood pressure was significantly reduced with 3 mg/kg, but unchanged with 0.3 mg/kg. The total atherosclerotic lesion size at the aortic sinus was reduced with 0.3 mg/kg compared with control, and additional reduction was proved with 3 mg/kg. The fibrotic change was not different among three groups, but MOMA-2-, malondialdehyde-, 4-hydroxy-2-nonenal-immunostained areas were reduced by telmisartan. As the mechanism, we revealed that both doses of telmisartan markedly reduced superoxide production from in situ vessels assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining. And NAD(P)H dependent oxidase activity in vessels was reduced by telmisartan. Further, 8-iso-prostaglandin F2alpha level, a systemic oxidative stress marker, obtained from urine and plasma samples were significantly reduced by telmisartan. Telmisartan reduced atherosclerosis in apolipoprotein E-deficient mice at least partly via the suppression of oxidative stress.
Atherosclerosis 2006 Jun
PMID:Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. 1615 44

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

Nitrate-based vasodilators (NBVs) are commonly used to treat multiple sequelae of atherosclerosis. A commonly used NBV, glyceryl trinitrate (GTN) is bioactivated by mitochondrial, class 2 aldehyde dehydrogenase (ALDH2). ALDH2 and other ALDHs are NAD(P)+-dependent enzymes critical to the detoxification of cytotoxic lipid-aldehydes elevated in atherosclerotic lesions, such as trans-4-hydroxy-2-nonenal (HNE). The GTN bioactivation step, however, inac-tivates ALDH2 and may alter the metabolism of these aldehydes. In this study, we tested the hypothesis that multiple ALDH enzymes are inhibited by different NBVs. ALDH2, ALDH3A, and ALDH5A were present in aorta with ALDH2 and ALDH3A localized to the smooth muscle layers. GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity. In contrast, isosorbide-2,5-dinitrate (ISDN, 1 microM) inhibited ALDH3 activity (1.1 +/- 0.4% of control) but did not inhibit ALDH2 activity even up to 50 microM ISDN. In homogenates of rat aorta, GTN (1 microM) inhibited the NAD+-dependent (41 +/- 5% of control) and NADP+-dependent (25 +/- 6% of control) detoxification of HNE. The inhibition of ALDH3A, but not ALDH2, could be prevented by the addition of dithiothreitol. These studies demonstrate that GTN and ISDN possess selectivity for ALDH inactivation with different mechanisms of inactivation.
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PMID:Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases. 1624 77

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

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress in atherogenesis. Growing evidence indicates that chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD). ROS mediate various signaling pathways that underlie vascular inflammation in atherogenesis from the initiation of fatty streak development through lesion progression to ultimate plaque rupture. Various animal models of oxidative stress support the notion that ROS have a causal role in atherosclerosis and other cardiovascular diseases. Human investigations also support the oxidative stress hypothesis of atherosclerosis. Oxidative stress is the unifying mechanism for many CVD risk factors, which additionally supports its central role in CVD. A main source of ROS in vascular cells is the reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase system. This is a membrane-associated enzyme, composed of five subunits, catalyzing the one-electron reduction of oxygen, using NADH or NADPH as the electron donor. This system is an important target for genetic investigations. Identification of groups of patients with genetically prone or resistant of oxidative stress is therefore an obvious target of investigation. A better understanding of the complexity of cellular redox reactions, development of a new class of antioxidants targeted to specific subcellular sites, and the phenotype-genotype linkage analysis for oxidative stress will likely be avenues for future research with regards to the broader use of pharmacological therapies in the treatment and prevention of CVD.
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PMID:Oxidative stress and atherosclerosis. 1675 57

The NAD(P)H oxidase is an enzyme assembled at the cellular membrane able to produce superoxide anion from NADH or NAD(P)H (nicotinamide adenine dinucleotide phosphate). It is one of the main sources of superoxide anion in cardiovascular tissues and its role in a variety of cardiovascular disorders such as atherosclerosis, cardiac hypertrophy, and endothelial dysfunction was recently proposed. Although, many factors and receptors were shown to lead to the activation of the enzyme, particulary the type 1 angiotensin receptor, the pathways involved are still widely unknown. Despite the identification of factors such as c-Src and protein kinase C implicated in the acute activation of NAD(P)H oxidase, the signalling involved in the sustained activation of the enzyme is probably far more complex than was previously envisioned. In this review, we describe the role of endothelin-1 in NAD(P)H oxidase signalling after a sustained stimulation by angiotensin II. Since most pathologies caused by an NAD(P)H oxidase overactivation develop over a relatively long period of time, it is necessary to better understand the long-term signalling of the enzyme for the development or use of more specific therapeutic tools.
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PMID:The interrelation of the angiotensin and endothelin systems on the modulation of NAD(P)H oxidase. 1684 87

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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PMID:Free radicals and antioxidants in normal physiological functions and human disease. 1697 5

Oxidative and nitrosative stress play an important role in the development of endothelial vascular dysfunction during early atherosclerosis. Oxidative stress activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in endothelial cells. In patients with atherosclerosis the level of oxidized LDL in the plasma is elevated. In oxidized LDL various oxysterols have been identified, such as 7-ketocholesterol (7K). 7K has been shown to induce PARP activation in microglial cells. The aim of the current study was to clarify the effects of 7K on the activity of endothelial PARP and on the endothelium-dependent relaxant function of blood vessels. We treated human umbilical vein endothelial (HUVEC) cells with 2-16 microg/ml 7K as well as vascular rings harvested from BALB/c mouse thoracic aorta with 90 microg/ml 7K for 2 h. A group of mice was treated with 7K subcutaneously for 1 week (10 mg/kg/day). We also conducted in vitro and in vivo experiments using pretreatment with buthionine sulphoximine (BSO), a glutathione-lowering agent. The activity of PARP was calculated by measurement of tritiated NAD incorporation. The activity of PARP increased significantly in 7K-treated HUVEC cells. After BSO pretreatment, this increase was higher. Isolated vascular rings demonstrated no change in endothelium-dependent relaxant function after 2 h of incubation with 7K, even after BSO pretreatment. In vivo treatment with 7K for 1 week had no effect on the relaxant function. Our experimental results suggest that although 7-ketocholesterol can activate PARP enzyme in endothelial cells, it is not sufficient on its own to cause impairment in the endothelium-dependent vascular reactivity.
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PMID:Effects of 7-ketocholesterol on the activity of endothelial poly(ADP-ribose) polymerase and on endothelium-dependent relaxant function. 1708 16


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