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)

Epidermal growth factor (EGF) has been shown to be a potent mitogen for vascular smooth muscle cells (VSMC) both in vitro and in vivo, thus contributing to the development of atherosclerosis and hypertension. Stimulation of Rho-family GTPases Rac/Cdc42 exerts pleiotropic cellular effects and have been demonstrated to contribute to EGF-induced proliferation in other cell systems. However, the effect of EGF on Rac/Cdc42 activation is unknown for VSMC. In the present report, we evaluated stimulation of Rac/Cdc42 by EGF in VSMC performing PAK-PBD binding assay. EGF treatment of VSMC induced time and concentration dependent binding of GTP-bound Rac1 to PAK-PBD peaking at 1 min and showing sustained activation up to 15 min. However, stimulation of Cdc42 could not be demonstrated. To further evaluate downstream effectors of Rac1 stimulation of p21-activated kinase (PAK) and c-Jun N-terminal kinase (JNK) by EGF was determined. In VSMC, EGF sequentially stimulated PAK, peaking at 5 min, and JNK, peaking at 15 min. Pretreatment of VSMC by EGF receptor specific tyrosine kinase inhibitor AG1478 and non-specific tyrosine kinase inhibitor genistein inhibited EGF-induced activation of Rac1, PAK and JNK, whereas tyrosine kinase inhibitors specific for Src (PP1) and specific for platelet-derived growth factor (AG1296) had no effect. Specific inhibition or Rac1 by NSC23766 attenuated EGF-induced [(3)H] thymidine incorporation in VSMC. Our data provide evidence for EGF-induced Rac1 activation and implicate PAK and JNK as downstream targets of Rac1 in EGF signal transduction in VSMC.
Atherosclerosis 2008 Jan
PMID:Epidermal growth factor stimulates Rac1 and p21-activated kinase in vascular smooth muscle cells. 1735 25

A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13-21 in a linkage study of early-onset CAD. We completed an association-mapping study across the 1-LOD-unit-down supporting interval, using two independent white case-control data sets (CATHGEN, initial and validation) to evaluate association under the peak. Single-nucleotide polymorphisms (SNPs) evenly spaced at 100-kb intervals were screened in the initial data set (N=468). Promising SNPs (P<.1) were then examined in the validation data set (N=514). Significant findings (P<.05) in the combined initial and validation data sets were further evaluated in multiple independent data sets, including a family-based data set (N=2,954), an African American case-control data set (N=190), and an additional white control data set (N=255). The association between genotype and aortic atherosclerosis was examined in 145 human aortas. The peakwide survey found evidence of association in SNPs from multiple genes. The strongest associations were found in three SNPs from the kalirin (KALRN) gene, especially in patients with early-onset CAD (P=.00001-00028 in the combined CATHGEN data sets). In-depth investigation of the gene found that an intronic SNP, rs9289231, was associated with early-onset CAD in all white data sets examined (P<.05). In the joint analysis of all white early-onset CAD cases (N=332) and controls (N=546), rs9289231 was highly significant (P=.00008), with an odds-ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P=.03) in 145 human aortas. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase and guanine-exchange-factor activity. KALRN and two other associated genes identified in this study (CDGAP and MYLK) belong to the Rho GTPase-signaling pathway. Our data suggest the importance of the KALRN gene and the Rho GTPase-signaling pathway in the pathogenesis of CAD.
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PMID:Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease. 1735 71

Shear stress changes play an important role in atheroma formation. This study focussed on atherogenic protein expression under non-uniform shear stress and the pharmacological modulation of shear-related endothelial dysfunction. Bifurcating flow-through cell culture slides were used to expose HUVECs to steady laminar or non-uniform shear stress for 18 h at 10 dyn/cm(2). Protein expression was determined by immunofluorescence, and quantified using MetaVue software. Laminar shear stress resulted in cell alignment, reduced F-actin fibers, and significant induction of endothelial nitric oxide synthase expression. Under non-uniform shear stress at bifurcations, minor upregulation of adhesion molecules was observed. Connective tissue growth factor (CTGF) was significantly downregulated by laminar shear stress and induced in cells exposed to non-uniform shear stress. CTGF upregulation by non-uniform shear stress was RhoA-dependent, because it was almost completely inhibited in cells transfected with dominant negative RhoA-N19, and when cells were treated with 1 micromol/L simvastatin during flow. Pre-incubation of HUVECs with inhibitors of Rho-associated kinase before exposure to flow significantly suppressed the CTGF induction in regions of non-uniform shear stress. In conclusion, non-uniform shear stress-dependent CTGF expression requires active RhoA and can be prevented pharmacologically. Interference with shear stress-induced protein expression may inhibit endothelial dysfunction in atheroprone vessel regions.
Atherosclerosis 2008 Jan
PMID:Pharmacological inhibition of RhoA signaling prevents connective tissue growth factor induction in endothelial cells exposed to non-uniform shear stress. 1745 38

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects," and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.
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PMID:Pleiotropic effects of statins and related pharmacological experimental approaches. 1720 Jul 29

Rho-kinase (ROCK) is one of the downstream effectors of the small G-protein Rho. The Rho-ROCK pathway has an important role in mediating various cellular functions, including contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, cytokinesis and gene expression, all of which are involved in the pathogenesis of cardiovascular disease. Indeed, vascular smooth muscle cells, endothelial cells, adventitial cells, cardiomyocytes and nerve cells all undergo pathophysiological changes through the ROCK pathway. Abnormal activation of this pathway is associated with the pathogenesis of various cardiovascular diseases such as hypertension, coronary and cerebral vasospasm, restenosis, atherosclerosis, stroke and heart failure, although the roles of the ROCK isoforms (ROCK1 and ROCK2) remain to be elucidated. In this article, we review the information about the therapeutic importance of the ROCK pathway and summarize the current status of the development of ROCK inhibitors.
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PMID:Development of Rho-kinase inhibitors for cardiovascular medicine. 1748 81

The relationships between cerebral and systemic endothelial (dys)function and between cerebral (dys)function and intima-media thickness (IMT) of carotid arteries in patients and healthy volunteers have not yet been clarified. In order to explore these issues, the authors performed a post hoc correlation analysis of cerebrovascular reactivity to L-arginine, a marker of cerebral endothelial function; flow-mediated dilatation (FMD), a marker of systemic endothelial function; and IMT of the carotid arteries, a marker of the extent of atherosclerosis. Correlations were analyzed in a heterogeneous group consisting of 20 patients with lacunar infarctions (LIs) and extensively impaired endothelial function, 21 patients with similar risk factors (SRs), but without LIs, and 21 healthy controls. Cerebrovascular reactivity to L-arginine was determined by the transcranial Doppler method (TCD), FMD by ultrasound measurements of the brachial artery after hyperemia, and IMT by measurement of the common carotid arteries. Analysis of correlations in the group of 62 subjects revealed that L-arginine reactivity, which was diminished in LI and SR patients, did not correlate with FMD, which was also diminished in both LI and SR patients (Rho = 0.10 with p = 0.458). On the contrary, a significant negative correlation was found between L-arginine reactivity and IMT (Rho = -0.30 with p = 0.015). In conclusion, our study investigating relations between cerebral and systemic endothelial dysfunction showed that cerebral endothelial function, determined by L-arginine reactivity, correlates well with the degree of atherosclerosis determined by IMT but does not correlate with FMD, suggesting that cerebral and systemic endothelial function may not be closely associated.
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PMID:Associations between systemic and cerebral endothelial impairment determined by cerebrovascular reactivity to L-arginine. 1749 63

The endothelial adherens junction (AJ) complex consisting of VE-cadherin and its associated catenins is a major determinant of fluid, solute, and plasma protein permeability of the vessel wall endothelial barrier. Impairment of endothelial barrier function contributes to cardiovascular diseases such as vascular inflammation and atherosclerosis. Adherens junctions disassemble in response to proinflammatory mediators, producing an increase in endothelial permeability; however, AJs also have the capacity to reassemble, leading to restoration of endothelial barrier function. Activation of Cdc42, a member of the Rho family of monomeric GTPases, is an essential signal regulating reannealing of AJs and reversal of the increase in endothelial permeability. The possibility of activating Cdc42 therapeutically represents a novel approach to prevent inflammatory diseases resulting from breakdown of the endothelial barrier. This review summarizes recent findings concerning the role of Cdc42 in restoring endothelial barrier integrity.
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PMID:Cdc42 regulates the restoration of endothelial adherens junctions and permeability. 1757 22

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

Macrophage-derived lipases are associated with atherosclerosis in human and animal studies. Despite numerous non-lipid-lowering effects of statins, their effect on macrophage LPL and endothelial lipase (EL) expression has not been investigated. In the present study, atorvastatin and simvastatin dose-dependently decreased LPL and EL expression as well as Rho, liver X receptor alpha (LXRalpha), and nuclear factor kappaB (NF-kappaB) activation in THP-1 macrophages. Atorvastatin-reduced LPL and EL expression was only partially recovered by mevalonate cotreatment, indicating that mechanisms independent of reductase inhibition may be present. By contrast, Rho activation by lysophosphatidyl acid further decreased LPL and EL expression in the presence or absence of atorvastatin. Another Rho activator, farnysyl pyrophosphate, decreased EL expression only in the absence of atorvastatin. LXRalpha activation by T0901317 and 22(R)-hydroxycholesterol not only rescued but also significantly increased LPL expression in the presence and absence of atorvastatin, respectively, whereas LXRalpha inhibition by 22(S)-hydroxycholesterol decreased LPL expression. By contrast, EL expression was suppressed by LXRalpha activation in the presence or absence of atorvastatin. NF-kappaB inhibition by SN50 was associated with an approximately 30% reduction of EL expression. Furthermore, atorvastatin treatment significantly attenuated the lipid accumulation in macrophages treated with oxidized LDL. We conclude that atorvastatin reduces LPL and EL expression by reducing the activation of LXRalpha and NF-kappaB, respectively.
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PMID:Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages. 1764 77

The Rho kinase (ROCK) isoforms, ROCK1 and ROCK2, were initially discovered as downstream targets of the small GTP-binding protein Rho. Because ROCKs mediate various important cellular functions such as cell shape, motility, secretion, proliferation, and gene expression, it is likely that this pathway will intersect with other signaling pathways known to contribute to cardiovascular disease. Indeed, ROCKs have already been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. However, it is not entirely clear how ROCKs are regulated, what some of their downstream targets are, and whether ROCK1 and ROCK2 mediate different cellular functions. Clinically, inhibition of ROCK pathway is believed to contribute to some of the cardiovascular benefits of statin therapy that are independent of lipid lowering (ie, pleiotropic effects). To what extent ROCK activity is inhibited in patients on statin therapy is not known, but it may have important clinical implications. Indeed, several pharmaceutical companies are already actively engaged in the development of ROCK inhibitors as the next generation of therapeutic agents for cardiovascular disease because evidence from animal studies suggests the potential involvement of ROCK in hypertension and atherosclerosis.
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PMID:Rho kinase (ROCK) inhibitors. 1766 11


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