UMLS:C0004153 - FACTA Search

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)

Diabetic angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of diabetic angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroangiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term diabetic complications.
...
PMID:The role of nitric oxide in the development of diabetic angiopathy. 1515 13

There is a complex pathophysiologic scenario involving nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the reduction in bioactivity of ENOS with subsequent impaired release of NO. An important mechanism is local enhanced degradation of NO by increased generation of reactive oxygen species and other free radicals, with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Novel molecular approaches have resulted in the development of new strains of mice lacking eNOS. These experimental models will help to understand how to implement NO-based therapies against atherosclerosis. L-arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. The target or goal for new drugs should be the complete restoration of NO-mediated signaling pathways in atherosclerotic arteries.
...
PMID:Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis. 1519 2

Ligusticum chuanxiong and Angelica sinensis have been widely used in traditional Chinese medicine to treat some pathological settings such as atherosclerosis and hypertension. We determined the protective effect of the extract of Ligusticum chuanxiong and Angelica sinensis (ELCAS) on human umbilical vein endothelial cells (ECV304) damage induced by hydrogen peroxide. ECV304 cells were pre-treated with ELCAS and exposed to 5 mM hydrogen peroxide. The results show that ELCAS dose- and time-dependently protected ECV304 cells against hydrogen peroxide damage and suppressed the production of reactive oxygen species (ROS). The decrement of ROS may be associated with increased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Western blot analysis revealed that ELCAS significantly increased the phosphorylation of ERK and promoted eNOS expression. These observations indicate that ELCAS protected ECV304 cells against hydrogen peroxide damage by enhancing the antioxidative ability, activating ERK and eNOS signaling pathway. Our data also provide new evidence of Ligusticum chuanxiong and Angelica sinensis in preventing both cardiovascular and cerebrovascular diseases.
...
PMID:Protective effect of Ligusticum chuanxiong and Angelica sinensis on endothelial cell damage induced by hydrogen peroxide. 1526 76

The role of genetic susceptibility to coronary artery disease (CAD) seems to be quite important in young patients. In the last years the attention has been focused on polymorphisms influencing some biological functions (coagulation and fibrinolysis, platelets, vascular function, lipid metabolism, inflammation). The study of prothrombotic polymorphisms has kindled a deep interest. The role of atherosclerosis and thrombosis is different in the different ages. In all the studies we examined, the polymorphism G20210A in the prothrombin gene was associated with an increased risk of acute myocardial infarction (AMI) in young people, especially when other risk factors were present. Contradictory results have been found in the studies on Factor V Leiden: according to many authors the activated protein C resistance (APCR) is associated with an increased risk of AMI only in smokers, above all if women. On the other hand, some polymorphisms of the Factor VII gene seem to be protective. Young AMI could be also caused by a reduction of the fibrinolytic activity, as it was found when the allele 4G in the promoter of plasminogen activator inhibitor (PAI) gene is present. The attention has also been focused on the effects of variations in genes that influence platelet functions. According to a metanalysis of studies published up to 1999, there is no association between the polymorphism PlA1/A2 of the GP IIIa gene and young AMI, whereas there is doubt about the role of the polymorphism in the GP IIb e GP Ib genes. Moreover, it seems to be present an association with the polymorphisms in the thrombopoietin gene (C4830A and A5713G). Also the role of some genes coding for proteins influencing the vascular functions has been valued. Few studies were performed on genetics of the renin-angiotensin-aldosterone system and the results are insufficient and contradictory, such as those about the association between the polymorphism G894T in the eNOS gene or the polymorphism C677T in the MTHFR gene and young AMI. Genes coding for proteins involved in the lipid metabolism have been closely examined. Many polymorphisms were discovered in the Apo B gene: the variant C-516T was found to be associated with increased LDL levels, whereas the results about the association between this and other polymorphisms in the same gene (I/D of LAL sequence, PvuII, MspI, Asp4311Ser) and young AMI are discordant. On the other hand, the variant e4 of the ApoE gene was associated with an increased risk of AMI at young age in many works. In the last years, a particular interest has kindled the study of the relationship between inflammation, atherosclerosis and CAD. Even if the studies performed are few, it was found an association between young AMI and polymorphism C-260T in the CD14 gene, between coronarics atherosclerosis and polymorphism A516C in the E Selectin gene or polymorphisms Leu125Val and Ser563Asn in the PECAM1 gene.
...
PMID:Genetic risk factors in myocardial infarction at young age. 1528 79

Concept of sequence and time of appearance of various effects of statins is presented. Apart from hypolipidemic action due to inhibition of HMG CoA reductase activity statins exert multiple pleiotropic effects. Combination of these effects makes statins a unique instrument for solution of global tasks of prevention and treatment of atherosclerosis and its consequences (ischemic heart disease etc.). Manifestations of various pleiotropic effects of statins appear after different time intervals and in most cases are not related to suppression of cholesterol synthesis in the body. First 3-4 months (first level of the statin cascade) are characterized mainly by activity of pleiotropic properties aimed at restoration of endothelial function. These properties are responsible for enhanced eNOS expression, antiischemic, antithrombotic and antiatherogenic effects. During same period of time stabilization of unstable atheromas takes place. Manifestations of second level of the cascade of statin action appear after 2 years of treatment. They are represented by retardation of progression and even partial regression of atheromatosis of coronary and peripheral arteries. Third level is signified by achievement of strategic aims of therapy with statins (in 4-5 years) -- lowering of total and cardiac mortality, reduction of number of cardiac complications. Forth level of the cascade is represented by beneficial influences on nonatherogenic cardiological phenomena and comprise hypotensive, antiarrhythmic and cardiotonic effects. And finally some other important properties of statins constitute the fifth level of the therapeutic cascade. These properties are responsible for effects directed at noncardiac pathology (prevention of diabetes, dementia, including dementia associated with Alzheimer's disease, fractures). Immunodepression, ability to reduce saturation of bile with cholesterol belong to this group of effects.
...
PMID:[Statins: therapeutic cascade of their effects]. 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

Cigarette-induced endothelial dysfunction could be an early mediator of atherosclerosis. In this study, we explored the mechanisms of cigarette smoke extract (CSE)-induced human aortic endothelial cells (HAEC) apoptosis. We found that 10-65% of HAECs underwent apoptotic changes when HAECs were exposed to 0.001-0.02 cigarette equivalent unit of CSE for 4 h. CSE activated the caspases-3 and 8, the p38 MAP kinase and stress activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK). Specific inhibitors of p38 MAP or SAPK/JNK reduced CSE-induced caspase activation. We further showed that eNOS pre-activation by L-arginine reduced endothelial apoptosis from 65% to 5%; and eNOS inhibition by N-omega-nitro-L-arginine methyl ester accentuated CSE-induced endothelial apoptosis. We suggest that appropriate endogenous NO production may be an important protective mechanism against smoking-induced endothelial damage.
...
PMID:Endogenous nitric oxide activation protects against cigarette smoking induced apoptosis in endothelial cells. 1567 Aug 37

The endothelial cell (EC) dysfunction is a common characteristic of various pathologies that include atherosclerosis, hypertension, and Fabry's disease. Aware of the role of eNO and ACE in EC dysfunction, we questioned whether polymorphism of eNOS and/or ACE gene may be a common denominator in these pathologies. Patients with CHD (108), HT (109), Fabry's disease (37) and healthy subjects (control, 141) were genotyped for the eNOSG894T by RFLP-PCR technique and for eNOS4b/a, and ACEI/D polymorphisms by PCR amplification. The results of these studies were statistically evaluated. Compared to controls, the frequency of the eNOSG894T (T allele) was higher in CHD (P=0.03) and Fabry (P=0.01), while the eNOS4b/a (a allele) in CHD (P=0.01) and HT patients (P=0.01). The proportion of the ACEI/D was similar in all subjects. In CHD patients at "low risk" of atherogenic factors, the frequency of the T and a alleles of eNOS gene was high (P=0.03 and 0.02, respectively). Carriers of the T allele of eNOSG894T were over-represented (P=0.04) in Fabry subgroup with renal failure. Compared to women, the eNOS894T alleles were more frequent (P=0.03) in men with CHD and HT, whereas ACE I/D in men (P=0.03) with HT. These findings suggest: (i) the frequency of eNOSG894T and/or eNOS4b/a is significantly associated with coronary dysfunction; (ii) eNOS4b/a confers a relatively high risk of hypertension in subjects with atherogenic risk factors; (iii) the frequency of eNOSG894T is high in Fabry hemizygotes with renal complications. Therefore, eNOS gene polymorphism represent a frequent risk factor for vascular abnormalities in CHD, HT and Fabry's disease, afflictions which have in common, the endothelial dysfunction.
...
PMID:Relationship of eNOS gene variants to diseases that have in common an endothelial cell dysfunction. 1578 71

Inflammation is pivotal in atherogenesis. Numerous prospective studies have shown that levels of high sensitive C-reactive protein (CRP) predict cardiovascular events. Recently, data suggests that CRP could be a mediator in atherothrombosis. Loss of pentameric symmetry in CRP has been shown to result in the formation of modified CRP (mCRP). The main aim of this study was to examine the biological effects of the native, pentameric form of CRP compared to a modified form in human aortic endothelial cells. Human pentameric native CRP (n-CRP) from two different sources (recombinant and serum) was purified and used. It was then subjected to EDTA chelation and urea treatment to prepare modified CRP (m-CRP). Purity of both n-CRP and m-CRP preparations was checked by gel electrophoresis. Both n-CRP and m-CRP were incubated with human aortic endothelial cells (HAEC) and biological activities was tested by assaying for interleukin-8 (IL-8), plasminogen activator inhibitor-1(PAI-1), cyclic GMP and prostaglandin F1-alpha. n-CRP significantly upregulated IL-8 at concentrations > or = 10 microg/mL while m-CRP upregulated IL-8 only at concentrations of 50 microg/mL (p < 0.05). PAI-1 levels were significantly increased to a greater extent with native compared to m-CRP (p < 0.05). While both decreased PGF1-alpha at concentrations of 50 microg/mL, the effect of native CRP was more pronounced and was evident at 10 microg/mL (p < 0.05). The most pronounced difference was observed with regard to inhibition of eNOS activity as assessed by cGMP which was observed at 10 microg/ml of native CRP but only at 50 microg/mL for m-CRP (native CRP versus mCRP: p < 0.001). Thus, native pentameric CRP compared to modified CRP exerts more potent atherogenic effects in human aortic endothelial cells.
Atherosclerosis 2006 Jan
PMID:Native pentameric C-reactive protein displays more potent pro-atherogenic activities in human aortic endothelial cells than modified C-reactive protein. 1589 19

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors protect the vasculature from inflammation and atherosclerosis by cholesterol dependent and cholesterol independent mechanisms. We hypothesized that HMG-CoA reductase inhibitors decrease exocytosis of Weibel-Palade bodies, endothelial cell granules whose contents promote thrombosis and vascular inflammation. We pretreated human aortic endothelial cells with simvastatin for 24 hours, then stimulated the cells with thrombin, and measured the amount of vWF released into the media. We then measured the effect of simvastatin on myocardial infarction in mice. Simvastatin decreased thrombin-stimulated Weibel-Palade body exocytosis by 89%. Simvastatin inhibited exocytosis in part by increasing synthesis of nitric oxide (NO), which S-nitrosylated N-ethylmaleimide sensitive factor (NSF), a critical regulator of exocytosis. Simvastatin treatment attenuated myocardial infarct size by 58% in wild-type but not eNOS knockout mice. Furthermore, simvastatin decreased endothelial exocytosis and neutrophil infiltration into ischemic-reperfused myocardium, which was mediated in part by P-selectin contained in Weibel-Palade bodies. However, simvastatin did not affect exocytosis and inflammation in myocardial infarcts of eNOS knockout mice. Inhibition of endothelial exocytosis is a novel mechanism by which HMG-CoA reductase inhibitors may reduce vascular inflammation, inhibit thrombosis, and protect the ischemic myocardium. These findings may explain part of the pleiotropic effects of statin therapy for patients with cardiovascular disease.
...
PMID:HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. 1590 63

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