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)

Oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases, including atherosclerosis, hypertension, heart failure, stroke and diabetes. ROS (reactive oxygen species) affect multiple tissues either directly or through NO depletion. ROS induce cardiovascular dysfunction by modulating cell contraction/dilation, migration, growth/apoptosis and extracellular matrix protein turnover, which contribute to vascular and cardiac remodelling. Of the several sources of ROS within the cardiovascular system, a family of multisubunit NADPH oxidases appears to be a predominant contributor of superoxide anion. Recent findings suggest a significant role of the genetic background in NADPH oxidase regulation. Common genetic polymorphisms within the promoter and exonic sequences of CYBA, the gene that encodes the p22(phox) subunit of NADPH oxidase, have been characterized in the context of cardiovascular diseases. This review aims to present the current state of research into these polymorphisms in their relationship to cardiovascular diseases.
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PMID:NADPH oxidase CYBA polymorphisms, oxidative stress and cardiovascular diseases. 1818 11

Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as postangioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and reactive nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing coexpression of iNOS and Nox in vascular smooth muscle demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen-activated protein kinases are important modulators of proinflammatory cytokine-dependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cdelta is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of nonphagocytic NADPH oxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merits further investigation.
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PMID:Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases. 1821 30

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycemia is an independent risk factor for the development of cardiovascular disease. We and others have previously demonstrated that high D-glucose induced apoptosis through activation of the bax-caspase proteases pathway in human EC and the potential contribution of hepatocyte growth factor, as an anti-apoptotic factor, to the pathogenesis of endothelial dysfunction. The anti-apoptotic action of HGF was due to bcl-2-upregulation and the phosphatidylinositol 3-kinase pathway, which is involved in Akt activation. Although it has been known for years that cardiovascular tissues can release a large amount ROS, including superoxide, hydrogen peroxide, and nitric oxide, the role of oxidative stress in atherogenesis has received increasing attention in recent years. Recent work strongly suggests that NADPH oxidase is a major source of superoxide in cardiovascular cells, and oxidative stress can be involved in the process of endothelial dysfunction. NADPH oxidase can be activated in hyperglycemia through the protein kinase C pathway. From the viewpoint of these molecular mechanisms, HMG-CoA reductase inhibitors (statins) might inhibit the high glucose-induced NADPH oxidase activation through inhibition of Rac activity and finally prevent the increase in ROS production in diabetes. A recent clinical trial suggested that statins prevent several vascular events in patients with type 2 diabetes without a high concentration of LDL-cholesterol. These pleiotropic effects of statins can be expected to improve endothelial dysfunction through nitric oxide production and/or an anti-oxidant effect in diabetic patients.
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PMID:Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. 1822 May 82

In diabetic patients the incidence of cardiovascular diseases (CVD) is higher compared with those without diabetes. This elevated incidence may be due to an increased prevalence of established risk factors, such as obesity, dyslipidemia and hypertension. However, several other determinants must be considered. Attention must be paid to the role that specific factors strictly related to diabetes, insulin-resistance and post-prandial hyperglycemia, play in the etiopathogenesis of CVD, as for example atherosclerosis. This review acknowledges the incidence of diabetes on cardiovascular diseases and atherosclerosis from endothelial dysfunction to plaque destabilization, suggesting that insulin resistance and postprandial hyperglycemia should be considered keys in the generation of these worst diabetic cardiovascular outcomes. It finds in hyperglycemia the primum movens that mediates the cascade of vascular damaging events from the beginning of ROS formation to plaque rupture, through increased inflammation. It also adds insights of why diverse therapeutic interventions, which have in common the ability to reduce oxidative stress and inflammation, can impede or delay the onset of complication of atherosclerosis in diabetic patients.
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PMID:Insulin resistance and postprandial hyperglycemia the bad companions in natural history of diabetes: effects on health of vascular tree. 1822 Jun 86

Overexpression of the gene for heme oxygenase (HO)-1 leads to a reduction in pressor responsiveness to angiotensin II (Ang II) in experimental animals. Using rat vascular smooth muscle cells (VSMCs), we tested whether YS 49 [1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits Ang II-stimulated proliferation of VSMCs via induction of HO-1. YS 49 induced HO-1 protein production in a dose-and time-dependent manner in VSMCs. Treatment with YS 49 significantly and dose-dependently inhibited Ang II-induced VSMC proliferation, ROS production, and phosphorylation of JNK, but not P38 MAP kinase or ERK1/2. The antiproliferation effect of YS 49 was reversed by pretreatment with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), or with hemoglobin, a carbon monoxide (CO) scavenger. Similarly, VSMC proliferation, ROS production and phosphorylation of JNK by Ang II were significantly inhibited in VSMCs transfected with the HO-1 gene. Thus, HO-1 and the HO-1 product CO play, at least in part, a crucial role in Ang II-stimulated VSMC proliferation through the regulation of ROS production and JNK phosphorylation. Therefore, YS 49 has potential as a therapeutic strategy for the pathogenesis of Ang II-related vascular diseases such as hypertension and atherosclerosis, via the induction of HO-1 gene activity.
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PMID:YS 49, 1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, regulates angiotensin II-stimulated ROS production, JNK phosphorylation and vascular smooth muscle cell proliferation via the induction of heme oxygenase-1. 1826 5

This study investigated the proapoptotic effects of oxidized low density lipoprotein (oxLDL), which plays a key role in atherogenesis, on normal fresh human monocytes isolated from peripheral blood (PBMs), on human monocyte-derived macrophages, and on U937 monocytic cell line. OxLDL were generated by hypochlorous acid (HOCl) treatment of native LDL. We demonstrated that HOCl-oxLDL (200 microg/ml) induced apoptosis in PBMs and U937 cells via the mitochondrial pathway, whereas it failed to induce apoptosis in human monocyte-derived macrophages. OxLDL-induced U937 cells apoptosis involved ROS generation, mitochondrial Bax translocation with a disruption of mitochondrial membrane potential, cytosolic liberation of cytochrome c and subsequently activation of caspases-9 and -3. The interference of ROS scavengers N-acetylcysteine and catalase with HOCl-oxLDL-induced apoptosis further supports the importance of mitochondrial ROS production in this process. Bcl-2 overexpression prevented Bax translocation whereas it failed to prevent ROS generation indicating that ROS is an upstream signal for inducing mitochondrial apoptotic damages. Because monocyte apoptosis could limit early atheroma formation, it will be interesting to identify the signaling pathway(s) induced by HOCl-oxLDL leading to ROS generation. In contrast, monocyte-derived macrophages, which resist to HOCl-oxLDL-induced oxidative stress, may promote atherosclerosis.
Atherosclerosis 2008 Oct
PMID:Role of reactive oxygen species and Bax in oxidized low density lipoprotein-induced apoptosis of human monocytes. 1828 75

Endothelial cells (ECs) damage is an initial and pivotal step in the formation of atherosclerosis. Endothelial progenitor cells (EPCs), which have been considered as the precursor of ECs, can migrate and home to the site of injured ECs to divide into mature ECs and keep the integrity of the endothelial monolayer. It has been shown that the number and function of EPCs are negatively correlated with various atherosclerotic risk factors. This finding may be explained partly by accelerated senescence of EPCs induced by telomere attrition or shortening owning to oxidative stress and accumulative ROS. However, elevated telomerase activity which extends the telomere cannot lead to cellular immortal in the presence of the cyclin-dependent kinase inhibitor p16(INK4a). Researchers have the opinion that senescence is the balance between the regeneration and cancer. High expression of phosphorylated p16(INK4a), which is caused by oxidative stress and accumulative ROS, can prevent tumor cells from unlimited division and becoming malignant ones by accelerating premalignant cells premature senescence. It has been demonstrated that the expression of p16(INK4a) increases remarkably with age due to oxidative stress and accumulative ROS in some stem and progenitor cells, and regulates these cells age-dependent senescence. It is observed that telomeres shortening exists in these cells. Therefore, it can be hypothesized that p16(INK4a), together with telomerase, may co-modulate EPCs senescence.
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PMID:Cyclin-dependent kinase inhibitor p16(INK4a) and telomerase may co-modulate endothelial progenitor cells senescence. 1834 32

Chronic kidney disease with hyperphosphatemia is associated with accelerated atherosclerosis and endothelial dysfunction. However, the contribution of high serum phosphate levels to endothelial injury is incompletely understood. The aim of this work was to evaluate the responses of endothelial cells to elevated levels of extracellular phosphate in vitro. High phosphate in concentrations similar to those observed in uremia-associated hyperphosphatemia (>2.5 mM) induced apoptosis in two endothelial cell lines (EAhy926 cells and GM-7373 cells). This effect was enhanced when cells were incubated for 24 h in the presence of 2.8 mM calcium instead of 1.8 mM. By treating cells with 0.5 or 1.0 mM phosphonoformic acid, an inhibitor of the phosphate transporter, death was completely prevented. The process of phosphate-induced apoptosis was further characterized by increased oxidative stress, as detected by increased ROS generation and disruption of the mitochondrial membrane potential at approximately 2 h after treatment, followed by caspase activation. These findings show that hyperphosphatemia causes endothelial cell apoptosis, a process that impairs endothelial integrity. Endothelial cell injury induced by high phosphate concentrations may be an initial event leading to vascular complications in patients with chronic kidney disease.
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PMID:Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. 1838 73

The susceptibility of fatty acids to oxidation is thought to be directly dependent on their degree of unsaturation. However, some in vitro and in vivo studies suggest that the relation between chemical structure and susceptibility to oxidation is not as straightforward as hypothesized from theoretical viewpoints. Indeed, long chain polyunsaturated fatty acids (LC-PUFAs) might be less oxidizable than others under specific experimental conditions. We investigated the free radical-scavenging potential of PUFA and the production of reactive oxygen/nitrogen (ROS/RNS) species by human aortic endothelial cells (HAECs) supplemented with different fatty acids. Fatty acid micelles scavenged superoxide in an unsaturation-dependent manner, up to eicosapentaenoic acid, which was the most effective fatty acid. Supplementation of HAEC with polyunsaturated fatty acids of the omega 3 series resulted in lower formation of ROS, as compared with cells supplemented with saturates, monounsaturates, or polyunsaturates of the omega 6 series. This effect was maximal at concentrations of 10muM. The effects of omega 3 fatty acids on reactive species production appear to be stronger when ROS were evaluated, as a milder, albeit significant effect was observed on RNS generation. Based on in vivo data showing reduced excretion of lipid peroxidation products after omega 3 intake and our data on ROS production and direct superoxide scavenging by LC-PUFAs, notably those of the omega 3 series, we propose that this series of fatty acid might act as indirect anti- rather than pro-oxidant in vascular endothelial cells, hence diminishing inflammation and, in turn, the risk of atherosclerosis and cardiovascular disease.
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PMID:Polyunsaturated fatty acids as antioxidants. 1858 47

Bisacurone, one of the active compounds of the traditionally used indigenous herb Curcuma longa Linne (Zingiberaceae), has anti-oxidant, anti-inflammatory, and anti-metastatic activities. We studied how the level of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules in the development of atherosclerosis as well as carcinogenesis and metastasis, might be affected by bisacurone in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Bisacurone dose-dependently inhibited TNF-alpha-mediated expression of VCAM-1. It showed significant suppressive effect on ROS generation in response to TNF-alpha stimulation and it blocked nuclear factor-kappa B (NF-kappaB) p65 translocation into the nucleus and phosphorylation of inhibitory factor kappaBalpha (IkappaBalpha). It also inhibited phosphorylation of Akt and PKC, which are upstream in the regulation of VCAM-1 by TNF-alpha. Furthermore, bisacurone decreased U937 monocyte and human oral cancer cell (Hep-2, QLL-I, SCC-15) adhesion to HUVECs stimulated by TNF-alpha, suggesting that it may inhibit the binding of these cells by regulating the expression of critical adhesion molecules by TNF-alpha. Thus, bisacurone may be beneficial in the treatment of inflammatory diseases, such as atherosclerosis, where inflammatory monocytes are involved in their pathology, and, moreover, in the development of tumors.
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PMID:Bisacurone inhibits adhesion of inflammatory monocytes or cancer cells to endothelial cells through down-regulation of VCAM-1 expression. 1860 74


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