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)

Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.
Atherosclerosis 2010 Jun
PMID:AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice. 2007 3

Inflammation-induced changes in the activity and expression of NADPH oxidases (Nox) play a key role in atherogenesis. The molecular mechanisms of Nox regulation are scantily elucidated. Since nuclear factor-kappaB (NF-kappaB) controls the expression of many genes associated to inflammation-related diseases, in this study we have investigated the role of NF-kappaB signaling in the regulation of Nox1 and Nox4 transcription in human aortic smooth muscle cells (SMCs). Cultured cells were exposed to tumor necrosis factor-alpha (TNFalpha), a potent inducer of both Nox and NF-kappaB, up to 24h. Lucigenin-enhanced chemiluminescence and dichlorofluorescein assays, real-time polymerase chain reaction, and Western blot analysis showed that inhibition of NF-kappaB pathway reduced significantly the TNFalpha-dependent up-regulation of Nox-derived reactive oxygen species production, Nox1 and Nox4 expression. In silico analysis indicated the existence of typical NF-kappaB elements in the promoters of Nox1 and Nox4. Transient overexpression of p65/NF-kappaB significantly increased the promoter activities of both isoforms. Physical interaction of p65/NF-kappaB proteins with the predicted sites was demonstrated by chromatin immunoprecipitation assay. These findings demonstrate that NF-kappaB is an essential regulator of Nox1- and Nox4-containing NADPH oxidase in SMCs. Elucidation of the complex relationships between NF-kappaB and Nox enzymes may lead to a novel pharmacological strategy to reduce both inflammation and oxidative stress in atherosclerosis and its associated complications.
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PMID:Transcriptional regulation of NADPH oxidase isoforms, Nox1 and Nox4, by nuclear factor-kappaB in human aortic smooth muscle cells. 2045 32

Elevated reactive oxygen species (ROS) formation in the vascular wall is a key feature of cardiovascular diseases and a likely contributor to oxidative stress, endothelial dysfunction and vascular inflammation. The NADPH oxidases are a family of ROS generating enzymes, of which four members (Nox1, Nox2, Nox4 and Nox5) are expressed in blood vessels. Numerous studies have demonstrated that expression and activity of at least two isoforms of NADPH oxidase - Nox1 and Nox2 - are up-regulated in animal models of hypertension, diabetes and atherosclerosis. However, these observations are merely suggestive of a role for NADPH oxidases in vessel pathology and by no means establish cause and effect. Furthermore, questions surrounding the specificity of current pharmacological inhibitors of NADPH oxidase mean that findings obtained with these compounds must be viewed with caution. Here, we review the literature on studies utilising genetically-modified mouse strains to investigate the roles of NADPH oxidases in experimental models of vascular disease. While several studies on transgenic over-expressing or knockout mice support roles for Nox1- and/or Nox2-containing oxidases as sources of excessive vascular ROS production and causes of endothelial dysfunction in hypertension, atherosclerosis and diabetes, there are still no published reports on the effects of genetic modification of Nox4 or Nox5 in vascular or indeed any other contexts. Further understanding of the roles of specific isoforms of NADPH oxidase in vascular (patho)physiology should provide direction for future programs aimed at developing selective inhibitors of these enzymes as novel therapeutics in cardiovascular disease.
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PMID:Nox isoforms in vascular pathophysiology: insights from transgenic and knockout mouse models. 2050 Sep 86

Endothelial cells are both the source and target of factors contributing to atherosclerosis. After the discovery of the endothelium-derived relaxing factor (EDRF) by Robert F. Furchgott in 1980 it soon became clear that endothelial cells also release vasoactive factors distinct from nitric oxide (NO) namely, endothelium-derived contracting factors (EDCF) as well as hyperpolarizing factors (EDHF). Vasoactive factors derived from endothelial cells include NO/EDRF, reactive oxygen species, endothelins and angiotensins which have either EDRF or EDCF functions, cyclooxygenase-derived EDCFs and EDRFs, and EDHFs. Endothelial factors are formed by enzymes such as NO synthase, cyclooxygenase, converting enyzmes, NADPH oxidases, and epoxigenases, among others, and participate in the regulation of vascular homeostasis under physiological conditions; however, their abnormal regulation due to endothelial cell dysfunction contributes to disease processes such as atherosclerosis, arterial hypertension, and renal disease. Because of recent changes in world demographics and the declining health status of the world's population, both aging and obesity as independent risk factors for atherosclerosis-related diseases such as coronary artery disease and stroke, will continue to increase in the years to come. Obesity and associated conditions such as arterial hypertension and diabetes are now also some of the primary health concerns among children and adolescents. The similarities of pathomechanisms activated in obesity and aging suggest that obesity--at least in the vasculature--can be considered to have effects consistent with accelerated, "premature" aging. Pathomechanisms as well as the clinical issues of obesity- and aging-associated vascular changes important for atherosclerosis development and prevention are discussed.
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PMID:Obesity and aging: determinants of endothelial cell dysfunction and atherosclerosis. 2063 93

Vascular dilatation is critically impaired in many diseases and is encountered by an upregulated endothelin receptor A (ETA) in the vasculature in association with a decline in nitric oxide bioavailability. Diabetic vasculopathy is characterized as a compromised vascular dilatation, implicated in many diabetic complications. It appears to be activated ETA and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase in the vasculature. Glucose-lowering agents do not always blunt these changes, as these changes may be progressive leading to the end stage of renal disease. The vascular insults by hypertension, hyperglycemia and aging may share the changes with diabetic vascular beds. Endothelin receptor antagonist CPU0213 and ingredients from plant origins such as CPU86017, p-benzyl-tetra-hydro-berberine are effective in attenuating vascular abnormality by normalizing changes of biomarkers in the vascular wall. The early sign of subclinical atherosclerosis presented as an intima media thickness in the carotid may indicate endothelium dysfunction. The reduced ABI (ankle brachial index) has been taken to predict patients at risk for cardiovascular and cerebrovascular events, and an increased risk of mortality from all causes and cardiovascular disease. An application of agents which suppress the activated ET-NADPH oxidase in the vascular wall is beneficial to attenuate vascular abnormalities. It is worth testing the activity of these agents further for the potential in relieving abnormal vascular activity, reducing the risk of morbidity and mortality in patients at risk.
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PMID:Role of endothelin receptor A and NADPH oxidase in vascular abnormalities. 2085 47

Abnormalities of lipid metabolism often lead to pathologic lipid accumulation in the vessel wall, oxidative and chronic inflammatory sequelae and the formation of atherosclerotic lesions, ultimately leading to clinical events. Oxidation of lipoproteins, and in particular low density lipoprotein (LDL), is a seminal even that mediates many pro-atherogenic and pro-inflammatory pathways. Many in vivo mechanisms exist to oxidize LDL, including transition metals such as divalent iron cations, heme, as well as a number of different enzyme systems, such as lipoxygenases, myeloperoxidase, NADPH oxidases, and nitric oxide synthases. Oxidized LDL is taken up in an unregulated fashion. By macrophages leading to foam cell formation, ultimately generating a potent pro-inflammatory milieu. Minimally modified LDL also induces proinflammatory effects in macrophages, including cytoskeletal rearrangements and macropinocytosis, generation of reactive oxygen species, survival of foam cells, reduced phagocytic capacity toward apoptotic cells, and expression of inflammatory genes, many of these effects mediated through toll-like receptor-4. Using the scientific knowledge gained from understanding these pathways, antibodies binding well-defined oxidation-specific epitopes have been generated and are being used in translational clinical applications. In particular, assays measuring oxidized phospholipids on apolipoprotein B-100 particles (OxPL/apoB) predict the presence and progression of femoral, carotid and coronary artery disease and predict new cardiovascular events independent of established risk factors. Human oxidation-specific antibodies have also been successfully used to image the extent and regression of experimental atherosclerotic lesions using nuclear and magnetic resonance imaging approaches. If validated and translated to humans, this imaging approach may provide a means to non-invasively detect, quantitate and monitor extent of atherosclerosis and potentially image high risk plaques. Further understanding of the role of oxidation of lipoproteins may allow more rational targeted diagnostic and therapeutic modalities in clinical applications.
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PMID:Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. 2122 65

Endothelial dysfunction and oxidative stress are the main pathophysiological mechanisms of several diseases such as hypertension, atherosclerosis, dyslipidemia, diabetes mellitus, cardiovascular disease, renal failure and ischemia-reperfusion injury. Reactive oxygen species (ROS) can modulate cellular function, receptor signals and immune responses in physiological conditions, but when present in excess, they mediate progressive endothelial damage through growth and migration of vascular smooth muscle and inflammatory cells, alteration of extracellular matrix, apoptosis of endothelial cells, activation of transcription factors (NFkB, AP-1), over-expression of inflammatory cytokines and adhesion molecules (ICAM-1, VCAM-1 , E-selectin). Recent evidences suggest that the major source of ROS is the NADPH-oxidase, especially activated by angiotensin II, shear stress and hyperglycemia. The unbalance between production of free radicals and the ability to neutralize them by antioxidant systems causes a condition of "oxidative stress". ROS alter vascular tone by increasing concentration of cytosolic calcium and especially causing a decreased availability of nitric oxide, the principal agent of endothelial function with vasodilating action. The data emerged from experimental and clinical studies confirm that endothelium-dependent vasodilation is altered in many diseases.
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PMID:[Oxidative stress and endothelial dysfunction]. 2131 49

Oxidative stress is implicated in diabetes. The NADPH oxidases are the main source of superoxide in phagocytic and vascular cells, and p22phox is a key subunit. Genetic variants of CYBA, the human p22phox gene, associate with cardiovascular disease. We investigated the association of the A640G polymorphism with diabetes and its impact on phagocytic NADPH oxidase-dependent superoxide production and subclinical atherosclerosis. We studied 1212 subjects in which clinical parameters including carotid intima-media thickness (cIMT) were assessed. The A640G polymorphism was genotyped by TaqMan probes. In 496 subjects, the NADPH oxidase-dependent superoxide production in peripheral blood mononuclear cells was assessed by chemiluminescence. The GG genotype prevalence was significantly higher in type 2 diabetic patients than in non-diabetic subjects. Peripheral blood mononuclear cells from diabetic GG patients presented higher NADPH oxidase-dependent superoxide production than those of diabetic AA/AG patients. Within the diabetic group, GG patients presented higher cIMT levels than AA/AG patients. The A640G CYBA polymorphism may be a marker of oxidative stress risk and may be indicative of subclinical atherosclerosis in type 2 diabetes.
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PMID:The A640G CYBA polymorphism associates with subclinical atherosclerosis in diabetes. 2162 50

The CYBA gene encodes the p22phox peptide, an essential subunit of vascular NADPH oxidases. The aim of the study was to analyze potential interactions between CYBA gene A640G polymorphism and traditional risk factors of atherosclerosis. We studied 320 subjects: 160 patients with coronary artery disease (CAD) and 160 controls. The results of interactions were interpreted on the basis of synergy index values (SI, SIM). The 640G allele interacted with cigarette smoking (SI = 2.02, SIM = 2.32). Even greater increase of the CAD risk was found whenever the 640G allele interacted with both smoking and hypercholesterolemia (SI = 2.70, SIM = 3.60). The results suggest that the A640G polymorphism may influence individual predispositions to CAD through interactions with smoking and hypercholesterolemia.
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PMID:The CYBA gene A640G polymorphism influences predispositions to coronary artery disease through interactions with cigarette smoking and hypercholesterolemia. 2177 68

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.
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PMID:Cross talk between mitochondria and NADPH oxidases. 2177 69


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