Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.
 ...
PMID:Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E. 1475 78

Hyperhomocysteinaemia has recently been recognized as a risk factor of cardiovascular disease. However, the action mechanisms of homocysteine (Hcy) are not well understood. Given that Hcy may be involved in the recruitment of monocytes and neutrophils to the vascular wall, we have investigated the role of Hcy in essential functions of human neutrophils. We show that Hcy increased superoxide anion (O2*-) release by neutrophils to the extracellular medium, and that this effect was inhibited by superoxide dismutase and diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase activity. The enzyme from rat peritoneal macrophages displayed a similar response. These effects were accompanied by a time-dependent increased translocation of p47phox and p67phox subunits of NADPH oxidase to the plasma membrane. We also show that Hcy increased intracellular H2O2 production by neutrophils, that Hcy enhanced the activation and phosphorylation of mitogen-activated protein kinases (MAPKs), specifically p38-MAPK and ERK1/2, and that the migration of neutrophils was increased by Hcy. Present results are the first evidence that Hcy enhances the oxidative stress of neutrophils, and underscore the potential role of phagocytic cells in vascular wall injury through O2*- release in hyperhomocysteinaemia conditions.
Atherosclerosis 2004 Feb
PMID:Homocysteine enhances superoxide anion release and NADPH oxidase assembly by human neutrophils. Effects on MAPK activation and neutrophil migration. 1501 32

Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2'-7' dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. A three times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy.
 ...
PMID:Changes in oxidative balance in rat pericytes exposed to diabetic conditions. 1509 Feb 67

There is evidence that LDL oxidation may render the lipoprotein atherogenic. The myeloperoxidase-hydrogen peroxide (MPO/H2O2) system of activated phagocytes may be involved in this process. Chloride is supposed to be the major substrate for MPO, generating reactive hypochlorous acid (HOCl), modifying LDL. The pseudo-halide thiocyanate (SCN-) has been shown to be a suitable substrate for MPO, forming reactive HOSCN/SCN*. As relatively abundant levels of SCN- are found in plasma of smokers--a well-known risk group for cardiovascular disease--the ability of SCN- to act as a catalyst of LDL atherogenic modification by MPO/H2O2 was tested. Measurement of conjugated diene and lipid hydroperoxide formation in LDL preparations exposed to MPO/H2O2 revealed that SCN- catalyzed lipid oxidation in LDL. Chloride did not diminish the effect of SCN- on lipid oxidation. Surprisingly, SCN inhibited the HOCl-mediated apoprotein modification in LDL. Nitrite--recently found to be a substrate for MPO--showed some competing properties. MPO-mediated lipid oxidation was inhibited by heme poisons (azide, cyanide) and catalase. Ascorbic acid was the most effective compound in inhibiting the SCN- -catalyzed reaction. Bilirubin showed some action, whereas tocopherol was ineffective. When LDL oxidation was performed with activated human neutrophils, which employ the MPO pathway, SCN- catalyzed the cell-mediated LDL oxidation. The MPO/H2O2/SCN- system may have the potential to play a significant role in the oxidative modification of LDL--an observation further pointing to the link between the long-recognized risk factors of atherosclerosis: elevated levels of LDL and smoking.
 ...
PMID:Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL. 1520 86

Diabetes mellitus (DM) is a common disease affecting over 124 million individuals worldwide. DM is associated with high risk of atherosclerosis and renal, neural, and ocular damage. Increased oxidant stress has been implicated in the pathogenesis of DM. An increase in serum ceruloplasmin (Cp) levels has also been reported in Type 2 DM. Cp permits the incorporation of iron into transferrin (Trf). Trf inhibits iron ion-dependent OHo formation from H2O2. Patients with diabetes have increased levels of plasma lipid peroxidation products. In this study, we evaluated 50 patients with Type 2 DM and 21 clinically healthy subjects. Patients were divided into two groups. Group I included 29 patients without diabetic complications, Group II 21 with diabetic complications. Serum Cp, Trf, C-reactive protein (CRP), triglyceride (TG), cholesterol (Chol), and malondialdehyde (MDA) levels are studied. Serum Cp, CRP, TG, Chol, and MDA levels in diabetic patients were significantly higher than those of controls. Trf levels were significantly lower in diabetic patients than those of the controls. Cp, CRP, HbA1C, and MDA levels in Group II were significantly higher than those of Group I. Our results indicate that oxygen free radicals are formed in DM and can result in diabetic complications and that a prooxidant/oxidant imbalance is involved in the tissue injury in DM and diabetic complications.
 ...
PMID:Levels of ceruloplasmin, transferrin, and lipid peroxidation in the serum of patients with Type 2 diabetes mellitus. 1520 35

Atherosclerosis is an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions including oscillatory shear stress (OS). OS exposure induces endothelial expression of bone morphogenic protein 4 (BMP4), which in turn may activate intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesion. OS is also known to induce monocyte adhesion by producing reactive oxygen species (ROS) from reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, raising the possibility that BMP4 may stimulate the inflammatory response by ROS-dependent mechanisms. Here we show that ROS scavengers blocked ICAM-1 expression and monocyte adhesion induced by BMP4 or OS in endothelial cells (ECs). Similar to OS, BMP4 stimulated H2O2 and O2- production in ECs. Next, we used ECs obtained from p47phox-/- mice (MAE-p47-/-), which do not produce ROS in response to OS, to determine the role of NADPH oxidases. Similar to OS, BMP4 failed to induce monocyte adhesion in MAE-p47-/-, but it was restored when the cells were transfected with p47phox plasmid. Moreover, OS-induced O2- production was blocked by noggin (a BMP antagonist), suggesting a role for BMP. Furthermore, OS increased gp91phox (nox2) and nox1 mRNA levels while decreasing nox4. In contrast, BMP4 induced nox1 mRNA expression, whereas nox2 and nox4 were decreased or not affected, respectively. Also, OS-induced monocyte adhesion was blocked by knocking down nox1 with the small interfering RNA (siRNA). Finally, BMP4 siRNA inhibited OS-induced ROS production and monocyte adhesion. Together, these results suggest that BMP4 produced in ECs by OS stimulates ROS release from the nox1-dependent NADPH oxidase leading to inflammation, a critical early atherogenic step.
 ...
PMID:Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. 1538 38

The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O2-*), hydrogen peroxide (H2O2), peroxynitrite (ONOO-*), nitric oxide (NO), and hydroxyl (*OH) radicals. The O2-* radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H2O2 and ONOO-*. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities ("redox signaling"); and 3) oxidative damage. Multiple enzymes can generate O2-*, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O2-* involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.
 ...
PMID:Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. 1547 99

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.
 ...
PMID:Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. 1554 38

Reactive oxygen species, such as superoxide anion (O2-) and hydrogen peroxide (H2O2), may act as second messengers of intracellular signaling and play a key role in the pathogenesis of atherosclerosis. The nuclear factor kappaB (NF-kappa B) is a redox-sensitive transcription factor that is involved in this process. The aim of the present study was to investigate the molecular mechanisms of action of statins on cultured vascular smooth muscle cells (VSMC) and monocytic cells (THP-1) under oxidative stress. In THP-1 and cultured VSMC, O2- caused an increase in NF-kappa B activation (P < 0.05) that was correlated with inhibitory I kappa B-alpha degradation. Atorvastatin or simvastatin decreased NF-kappa B activation induced by oxidative stress by around 50% in both cell types and was correlated with the I kappa B-alpha levels. In monocytes, O2- increased I kappa B kinase (IKK)-1 and IKK-2 activity (P < 0.05) and p38 and p42/44 activation and phosphorylation, which was reduced by statins. PD 98059 (p42/44 inhibitor) and SB20358 (p38 inhibitor) decreased NF-kappa B binding activity and prevented I kappa B-alpha degradation. However, we only observed a reduction in IKK-1 and IKK-2 activity with PD98059. Statins diminish NF-kappa B activation elicited by oxidative stress through the inhibition of IKK-1/-2, p38, and p42/44 activation. These data may help to further understand the molecular mechanisms of statins in cardiovascular disease.
 ...
PMID:HMG-CoA reductase inhibitors reduce I kappa B kinase activity induced by oxidative stress in monocytes and vascular smooth muscle cells. 1582 43

Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O2*-) and hydrogen peroxide (H2O2) appear most important in redox signaling. Whereas O2*- predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO*), H2O2 influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H2O2 in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase-derived H2O2 amplifies its own production. Recent studies have shown that H2O2 stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H2O2-dependent pathological signaling in vascular cells, thus contributing to vascular disease development. The latest progress on Nox functions in vascular cells is also discussed [Nox for NAD(P)H oxidases, representing a family of novel NAD(P)H oxidases].
 ...
PMID:NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease. 1586 Jul 62


<< Previous 1 2 3 4 5 6 7 8 9 10