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)

PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235+/-60%) and the bone marrow (166+/-30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231+/-21% (n=24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246+/-73% and increased expression of telomere repeat-binding factor 2 by 320+/-50%. In vivo neoangiogenesis was increased two-fold (214+/-42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65+/-2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H(2)O(2)-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases.
Atherosclerosis 2007 May
PMID:The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. 1687 72

Oxidative modification of LDL accumulated in the subendothelial space is a critical step in atherogenesis. Mouse strains C57BL/6 (B6) and BALB/c differ markedly in atherosclerosis susceptibility. We sought to determine whether variation of endothelial cells in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitutes a genetic component in atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining induction of monocyte chemotactic protein-1, macrophage-colony stimulating factor, and vascular cell adhesion molecule-1. Both strains exhibited comparable endothelial responses to MM-LDL, whereas BALB/c mice had an increased rate of oxidizing LDL compared with B6 mice. To examine whether endothelial nitric oxide synthase (eNOS) contributed to the difference in LDL oxidation, cells were incubated with native LDL in the presence or absence of N(Omega)-nitro-l-arginine methyl ester (l-NAME), a specific NOS inhibitor. Although l-NAME significantly inhibited endothelial cell-mediated LDL oxidation, it failed to abolish the difference between the strains. In contrast, Baicalein, a specific 12/15 lipoxygenase inhibitor, abolished the difference in LDL oxidation. Thus, the paradoxical increase in LDL oxidation by endothelial cells is attributable to higher oxidant activity of 12/15-lipoxygenase in BALB/c mice and endothelial cells appear unlikely to be a source of the resistance to atherosclerosis.
Atherosclerosis 2007 Jun
PMID:Paradoxical increase in LDL oxidation by endothelial cells from an atherosclerosis-resistant mouse strain. 1691 36

Senescence may contribute to the pathogenesis of atherosclerosis. Although the bioavailability of nitric oxide (NO) is limited in senescence, the effect of NO on senescence and its relationship to cardiovascular risk factors have not been investigated fully. We studied these factors by investigating senescence-associated beta-galactosidase (SA-beta-gal) and human telomerase activity in human umbilical venous endothelial cells (HUVECs). Treatment with NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO) and transfection with endothelial NO synthase (eNOS) into HUVECs each decreased the number of SA-beta-gal positive cells and increased telomerase activity. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the effect of eNOS transfection. The physiological concentration of 17beta-estradiol activated hTERT, decreased SA-beta-gal-positive cells, and caused cell proliferation. However, ICI 182780, an estrogen receptor-specific antagonist, and L-NAME each inhibited these effects. Finally, we investigated the effect of NO bioavailability on high glucose-promoted cellular senescence of HUVECs. Inhibition by eNOS transfection of this cellular senescence under high glucose conditions was less pronounced. Treatment with L-arginine or L-citrulline of eNOS-transfected cells partially inhibited, and combination of L-arginine and L-citrulline with antioxidants strongly prevented, high glucose-induced cellular senescence. These data demonstrate that NO can prevent endothelial senescence, thereby contributing to the anti-senile action of estrogen. The ingestion of NO-boosting substances, including L-arginine, L-citrulline, and antioxidants, can delay endothelial senescence under high glucose. We suggest that the delay in endothelial senescence through NO and/or eNOS activation may have clinical utility in the treatment of atherosclerosis in the elderly.
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PMID:Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. 1707 48

Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). As a consequence, oxygen reduction uncouples from NO synthesis, thereby rendering NOS to a superoxide-producing pro-atherosclerotic enzyme. Supplementation with BH(4) corrects eNOS dysfunction in several animal models and in patients. Administration of high local doses of the antioxidant L-ascorbic acid (vitamin C) improves endothelial function, whereas large-scale clinical trials do not support a strong role for oral vitamin C and/or E in reducing cardiovascular disease. Statins, angiotensin-converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress. Finally, novel approaches are being tested to block pathways leading to oxidative stress (e.g. protein kinase C) or to upregulate antioxidant enzymes.
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PMID:Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. 1713 97

Functional changes of the vessel wall--specifically dysfunction of endothelial cells--may precede the formation of frank plaques at the initiation of atherosclerosis. Clinically endothelial function and dysfunction can be measured by angiography or ultrasound techniques. Another possibility is the measurement of circulating markers of endothelial dysfunction in human plasma, such as the endogenous NOS inhibitor ADMA (asymmetric dimethylarginine). In our recent studies we were able to show that ADMA accumulates in the presence of metabolic changes such as hyperhomocysteinemia, insulin resistance and type-2 diabetes, and that these elevations of plasma ADMA correlate well with the amount of endothelial dysfunction and with NO bioavailability. Furthermore ADMA was shown to be dynamically regulated and to play an important patho-physiologic role in myocardial ischemia and reperfusion. Thus, measurements of plasma ADMA in patients could help to screen for manifestations of atherosclerosis. Moreover attempts to reduce plasma and tissue ADMA could potentially play an important role in the treatment of endothelial dysfunction, atherosclerosis, but also of ischemia reperfusion injury.
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PMID:[Asymmetric dimethyl arginine (ADMA): a novel cardiovascular risk factor?]. 1734 60

Recent large-scale epidemiological studies have documented a strong association between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). This observation has two important scientific and clinical aspects: (i) to reveal the pathomechanism linking LUTS and ED and (ii) to consider this fact in the individual approach for diagnosis and management of these two disorders. The following hypotheses are under investigation to explain the relation between LUTS and ED: (i) an increased Rho-kinase activation, (ii) an alpha-adrenergic receptor imbalance, (iii) a decrease of NOS/NO in the endothelium, (iv) atherosclerosis affecting the small pelvis and (v) an autonomic hyperactivity, each affecting simultaneously bladder, prostate and penis. According to a recent randomized trial, sildenafil has a positive effect on LUTS yet not on uroflowmetry in men with LUTS and ED. Although further trials are mandatory, phosphodiesterase-5 inhibitors might play a role in the management of LUTS in the future. alpha-Blockers have no relevant effect on erectile function, tamsulosin leads to retrograde ejaculation in up to 10%. 5alpha-Reductase inhibitors are associated with ED, loss of libido and reduction of ejaculate volume in up to 10%. Transurethral and open prostatectomy induce retrograde ejaculation in up to 90% of patients while their impact on erectile function is still controversially discussed. Minimal invasive treatment options (laser prostatectomy, transurethral microwave thermotherapy) have a lower rate of retrograde ejaculation in the range of 20-70%. LUTS and ED are strongly linked although the exact mechanism is poorly understood. Men seeking for help for LUTS/benign prostatic hyperplasia should be assessed for different aspects of sexual dysfunction and informed regarding the impact of medication and surgery on sexual health.
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PMID:Lower urinary tract symptoms and erectile dysfunction; links for diagnosis, management and treatment. 1761 8

Cannabinoid drugs exert their effects primarily through activation of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors have been implicated in a number of cardiovascular processes, including vasodilation, cardiac protection, modulation of the baroreceptor reflex in the control of systolic blood pressure, and inhibition of endothelial inflammation and the progress of atherosclerosis in a murine model. These effects are mainly mediated through central and peripheral nervous system CB1 receptors, vascular CB1 receptors and immune cell CB2 receptors. Relevant cellular effects include: the inhibition of neurotransmitter release in the nucleus tractus solitarius and in peripheral adrenergic neurons; regulation of NOS activity in vascular beds; inhibition of vascular smooth muscle cell excitability; regulation of endothelial cell migration and proliferation; and effects on immune cell proliferation, activation, and inflammatory functions. We review the pre-clinical evidence for beneficial effects of cannabinoid drugs in a range of vascular and cardiovascular pathologies. We also discuss the clinically relevant potential of cannabinoids.
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PMID:Cannabinoids and cardiovascular disease: the outlook for clinical treatments. 1762 61

Beta-actin is traditionally considered a structural protein that organizes and maintains the shape of nonmuscle cells, although data now indicate that beta-actin is also a signaling molecule. beta-actin is directly associated with nitric oxide synthase type 3 (NOS-3) in endothelial cells and platelets, and this interaction increases NOS-3 activity and the affinity of NOS-3 for heat shock protein 90 kD (Hsp90). The beta-actin-induced increase in NOS-3 activity may be caused directly by beta-actin, the binding of Hsp90 to NOS-3, or both. Alterations in the interaction between beta-actin and NOS-3 could be caused by changes either in the availability of beta-actin or in the affinity of NOS-3 for beta-actin, and these alterations probably contribute to vascular complications and platelet aggregation. Studies examining the interactions between NOS-3, beta-actin, and Hsp90 could potentially lead to the discovery of effective peptides for the treatment of diseases associated with impaired NOS-3 activity and nitric oxide release, such as systemic and pulmonary hypertension, atherosclerosis, and thrombotic diseases.
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PMID:Beta-actin: a regulator of NOS-3. 1787 10

Atherosclerosis is a chronic disease triggered by lipid disturbances, endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to initiate inflammatory immunity. We investigated the role of statins and the mevalonate pathway on DC invasion. DC incubation with atorvastatin (ATV; 0.05-1 microM) for 24h decreased DC adhesion capacity. DC invasion (adhesion/transmigration) was decreased after exposing DCs to low and moderate concentrations of statins, which was reversible by mevalonate (but not geranyl- or farnesyl-pyrophosphate) and cholesterol. Inhibition of the phosphoinositide 3-kinase (with wortmannin) and inhibition of the NO-synthase (with asymmetric dimethyl ADMA) partially reversed statin-mediated effects. High-dose statins markedly decreased DC invasion, which was reversible by adding geranyl pyrophosphate and cholesterol. Inhibition of geranylgeranyltransferase but not inhibition of farnesyltransferase significantly decreased DC invasion. Statin-mediated alteration in DC-cholesterol synthesis and subsequent activation of the Akt/NOS pathway accounts for the statin-induced decrease in DC invasion at low-moderate concentrations (0.05-0.5 microM). Additionally, at high statin concentrations (1 microM) DC invasion is reduced by inhibition of protein geranylgeranylation. As DCs control immunity, regulating DC/endothelial cell interaction by statins may have relevance to inflammation and atherogenesis.
Atherosclerosis 2008 Mar
PMID:Dual mode of HMG-CoA reductase inhibition on dendritic cell invasion. 1788 31

Endothelial dysfunction and atherosclerosis are associated with an inflammation-induced decrease in endothelial nitric oxide synthase (eNOS) expression. Based on the differences between hydrophobic and hydrophilic statins in their reduction of cardiac events, we analyzed the effects of rosuvastatin and cerivastatin on eNOS and inducible NO synthase (iNOS) expression and NOS activity in TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC). Both statins reversed down-regulation of eNOS mRNA and protein expression by inhibiting HMG-CoA reductase and isoprenoid synthesis. Cerivastatin tended to a more pronounced effect on eNOS expression compared to rosuvastatin. NOS activity - measured by conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline - was enhanced under treatment with both drugs due to inhibition of HMG-CoA reductase. Statin-treatment reduced iNOS mRNA expression under normal conditions, but had no relevant effects on iNOS mRNA expression in cytokine-treated cells. Rosuvastatin and cerivastatin reverse the detrimental effects of TNF-alpha-induced down-regulation in eNOS protein expression and increase NO synthase activity by inhibiting HMG-CoA reductase and subsequent blocking of isoprenoid synthesis. These results provide evidence that statins have beneficial effects by increasing eNOS expression and activity during the atherosclerotic process.
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PMID:Isoprenoid depletion by statins antagonizes cytokine-induced down-regulation of endothelial nitric oxide expression and increases NO synthase activity in human umbilical vein endothelial cells. 1792 46


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