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)

Lipoprotein associated phospholipase A2 (Lp-PLA2), a biomarker of oxidation and inflammation, has been associated with increased coronary heart disease (CHD) risk. To date, data examining the effect of HMG CoA reductase inhibitors on Lp-PLA2 are few. We evaluated the effect of pravastatin 40 mg daily versus placebo on Lp-PLA2 levels among 481 subjects free of cardiovascular disease (pravastatin N=246 and placebo N=235) who participated in the Pravastatin Inflammation/CRP Study (PRINCE). After 12 weeks, Lp-PLA2 levels decreased by 22.1% among pravastatin treated participants and by 7.8% among those randomized to placebo (p<0.001). These results were similar in all subgroups evaluated according to age, blood pressure, lipid parameters, diabetic status, smoking status, aspirin use, body mass index and gender. There were correlations between change in Lp-PLA2 levels and baseline Lp-PLA2 levels (r=-0.63, p<0.001), total cholesterol change (r=-0.26, p<0.001), LDL-C change (r=-0.32, p<0.001) and C-reactive protein (CRP) change (r=-0.13, p=0.05). Multivariate linear regression models that assessed the relationship between the log difference in Lp-PLA2 at 12 weeks and treatment revealed a beta-coefficient of 0.15 for the treatment variable (p<0.01). However, adjustment for change in LDL-C substantially attenuated the beta-coefficient associated with treatment to 0.07 (P<0.005) and after additional control for other potential confounders, the effect of treatment was no longer significant. Thus, Lp-PLA2 levels were significantly reduced at 12 weeks by pravastatin, an effect that was significantly related to LDL cholesterol reduction accounting for about 6% of the variability in this response. Moreover, pravastatin induced reduction in Lp-PLA2 was no longer significant after taking the latter into account.
Atherosclerosis 2005 Sep
PMID:The effect of statin therapy on lipoprotein associated phospholipase A2 levels. 1598 58

Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates pro-inflammatory molecules from oxidized LDL. We examined the association between Lp-PLA2 plasma concentrations and risk of stable coronary artery disease (CAD) in a large case-control study and further assessed the relationship between Lp-PLA2 and various lipid, inflammatory and hemostatic parameters. Lp-PLA2 concentrations were measured in 312 patients with CAD and in 479 age- and gender-matched blood donors. Various sensitive inflammatory and hemostatic markers and a complete lipoprotein profile were obtained. Lp-PLA2 concentrations were significantly higher in cases than in controls (296.1 ng/mL versus 266.0 ng/mL, p<0.0001). In multivariable logistic regression, the age- and gender-adjusted OR for the presence of CAD was 1.61 (95% CI, 1.07-2.44) if the top quartile of the Lp-PLA2 distribution was compared to the bottom quartile. Adjustment for traditional cardiovascular risk factors and statin use resulted in an OR of 2.04 (95% CI, 1.19-3.48). After additional controlling for vWF, the OR was slightly attenuated but still remained statistically significant (OR 1.91; 95% CI, 1.12-3.28). Thus, elevated Lp-PLA2 concentrations were associated with the presence of stable CAD, independent of various biochemical markers. Our results support the hypothesis that Lp-PLA2 may be a novel, independent risk marker for CAD.
Atherosclerosis 2005 Sep
PMID:Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis. 1611 90

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.
Atherosclerosis 2006 Nov
PMID:Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. 1643 75

Despite substantial progress in preventing adverse cardiovascular events with current therapeutic strategies, there remains an extensive residual risk of clinical events, particularly in high-risk patients. Because of the evidence implicating inflammation in the pathogenesis of atherosclerosis, identifying and targeting inflammatory pathways could help further reduce cardiovascular risk. There has been controversy regarding the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in atherosclerosis, partly because of the lack of simple animal models with a human-like pattern of Lp-PLA2 lipoprotein distribution. However, accumulating evidence from pathology, biology and epidemiology studies favors a pro-atherogenic rather than an atheroprotective role for the enzyme. In particular, Lp-PLA2 might play an important role in plaque vulnerability. As a result, additional studies are warranted to determine whether Lp-PLA2 inhibition improves plaque stability and ultimately clinical outcomes for high-risk patients.
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PMID:Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target. 1649 53

Lipid mediators such as prostaglandin E2 (PGE2) play a central role during atherogenesis as a consequence of inflammation. PGE2 is produced from phospholipids by a cascade of enzymatic reactions involving phospholipase A2 (PLA2), cyclooxygenase (COX), and prostaglandin E synthase (PGES). It is released by several cell types, including vascular smooth muscle cells (VSMCs). Recent work has shown that the secretory PLA2-IIA (sPLA2-IIA), the most abundant isoform of secreted PLA2 in VSMCs, acts as a potent cytokine and activates VSMCs through a positive feedback loop. High mobility group protein 1 (HMGB1), also known as amphoterin, is a ubiquitous protein that plays various roles in the nucleus. HMGB1 is released by necrotic cells and by immune cells in response to various inflammatory mediators and acts as a potent proinflammatory cytokine. The present study investigates the role of HMGB1 in the activation of sPLA2-IIA expression and PGE2 production in VSMCs. Recombinant HMGB1 slightly activated the sPLA2-IIA, COX-2, and mPGES-1 genes but dramatically stimulated these genes in VSMCs that had been incubated with the proinflammatory cytokine IL-1beta for 24 h. This effect was accompanied by significantly increased PGE2 release. Induction of the three known receptors of HMGB1, namely RAGE, TLR-2, and TLR-4, by IL-1beta suggests that proinflammatory cytokines sensitize VSMCs to HMGB1. This provides new insights into the role of HMGB1 in VSMCs, suggesting it may be essential for the progression of atherosclerosis.
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PMID:Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta. 1680 71

Identifying blood biomarkers may be of particular value in neurologic disorders such as stroke because of the difficulty in directly studying the brain and its blood vessels. Markers of brain injury, inflammation, excitotoxicity, and oxidative damage have been evaluated for their value in stroke diagnosis, treatment, and management, but none have proved to be sensitive or specific enough for routine clinical use. However, new cellular and molecular profiling approaches using the peripheral blood offer the potential for identifying panels of genes and proteins by increasing specificity while maintaining sensitivity. Furthermore, the first biomarker for predicting stroke risk associated with atherosclerosis (lipoprotein-associated phospholipase A2) was recently approved by the United States Food and Drug Administration. The ultimate aim for stroke biomarkers is to develop rapid, easy to use, widely available, and inexpensive diagnostic tests that can be used in the clinic and in clinical trials.
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PMID:Blood biologic markers of stroke: improved management, reduced cost? 1682 91

Lysophosphatidylcholine (LPC) is the major bioactive lipid component of oxidized LDL, thought to be responsible for many of the inflammatory effects of oxidized LDL described in both inflammatory and endothelial cells. Inflammation-induced transformation of vascular smooth muscle cells from a contractile phenotype to a proliferative/secretory phenotype is a hallmark of the vascular remodeling that is characteristic of atherogenesis; however, the role of LPC in this process has not been fully described. The present study tested the hypothesis that LPC is an inflammatory stimulus in coronary artery smooth muscle cells (CASMCs). In cultured human CASMCs, LPC stimulated time- and concentration-dependent release of arachidonic acid that was sensitive to phospholipase A2 and C inhibition. LPC stimulated the release of arachidonic acid metabolites leukotriene-B4 and 6-keto-prostaglandin F1alpha, within the same time course. LPC was also found to stimulate basic fibroblast growth factor release as well as stimulating the release of the cytokines GM-CSF, IL-6, and IL-8. Optimal stimulation of these signals was obtained via palmitic acid-substituted LPC species. Stimulation of arachidonic acid, inflammatory cytokines and growth factor release, implies that LPC might play a multifactorial role in the progression of atherosclerosis, by affecting inflammatory processes.
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PMID:Lysophosphatidylcholine induces inflammatory activation of human coronary artery smooth muscle cells. 1689 35

In this study, niacin was added to existing therapy for 3 months in 54 subjects with stable coronary artery disease. Average total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were similar between groups. Three months of niacin treatment increased total HDL by 7.5% and decreased triglycerides by 15% compared with baseline values (p <0.005 for each), whereas total cholesterol and LDL levels remained unchanged. Addition of niacin resulted in a 32% increase in large-particle HDL (p <0.001), an 8% decrease in small-particle HDL (p = 0.0032), an 82% increase in large-particle LDL (p = 0.09), and a 12% decrease in small-particle LDL (p = 0.008). Niacin decreased lipoprotein-associated phospholipase A2 and C-reactive protein levels (20% and 15%, respectively, p <0.05 for the 2 comparisons). No significant changes from baseline were seen in any tested parameter in subjects who received placebo. In conclusion, addition of niacin to existing medical regimens for patients with coronary artery disease and already well-controlled LDL levels favorably improves the distribution of lipoprotein particle sizes and inflammatory markers in a manner that would be expected to confer atheroprotection. The effect of altering lipoprotein particle distribution and inflammatory markers on surrogate markers of atherosclerosis and clinical cardiovascular events in this population remains unclear.
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PMID:Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. 1695 Jan 75

Accumulation and modification of low density lipoproteins (LDL) within the vessel wall represent key events in atherogenesis. Secretory phospholipase A2 type IIA (sPLA2-IIA) modulates the enzymatic process of LDL-modification and was recently identified as an independent predictor of coronary events in patients with coronary artery disease (CAD). Angiotensin II (ANG II) type 1 (AT1)-receptor blockade reduces LDL-modification and atherosclerotic plaque formation in rodent and primate models of atherosclerosis. Therefore, we assessed whether ANG II via its AT1-receptor enhances sPLA2-IIA-dependent lipid peroxidation in vitro and in patients with CAD. Stimulation of rat aortic smooth muscle cells with ANG II (10(-7) mol/L) enhanced sPLA2-IIA protein expression, activity as well as LDL-peroxidation, determined by western blot, activity assay and malondialdehyde (MDA)-assay and diene formation, respectively, and were blunted by AT1-receptor blockade (Losartan, 10(-5) mol/L). In addition, ANG II-induced sPLA2 activity and LDL-peroxidation were abolished by the sPLA2-IIa activity inhibitor LY311727 (10(-5) mol/L). To evaluate a potential clinical implication, patients (n=18) with angiographically documented CAD were treated with the AT1-receptor blocker Irbesartan (IRB; 300 mg/d) for 12 weeks. Blood samples were obtained from patients pre- and post-treatment and from healthy volunteers. SPLA2-IIA serum level and activity, circulating antibodies against oxidized LDL (oxLDL), oxLDL and MDA were determined in patients and found to be significantly increased compared to healthy volunteers. IRB therapy reduced these markers of inflammation, whereas total cholesterol, HDL- and LDL-fractions remained unchanged. ANG II may elicit pro-atherosclerotic effects via type IIA sPLA2-dependent LDL-modifications. Chronical AT1-receptor blockade reduces sPLA2-IIA level and activity and subsequently lipid peroxidation. Theses findings represent a novel anti-atherosclerotic mechanism and imply that AT1-receptor blockade elicits anti-atherosclerotic potencies even in the absence of plasma cholesterol reduction.
Atherosclerosis 2007 Sep
PMID:Angiotensin II type 1-receptor antagonism prevents type IIA secretory phospholipase A2-dependent lipid peroxidation. 1706 18

Obesity and inactivity are associated with endothelial dysfunction that may contribute to the development of atherosclerosis. We examined the effects of a short-term lifestyle intervention on circulating biomarkers of endothelial health. Nineteen overweight or obese (mean body mass index (BMI): 28.9 +/- 0.7 kg/m2) men and women underwent 6 weeks of body mass reduction induced by moderate energy restriction (approximately 750 kcal/d; 1 kcal = 4.184 kJ) and aerobic training (approximately 400 kcal/d). Fasting serum samples were collected at baseline and after reduction in body mass (week 6) to assess concentrations of nitrotyrosine (NT), secretory phospholipase A2 (sPLA2), and soluble intracellular adhesion molecule-1 (sICAM-1). Body mass was significantly reduced from 81.3 +/- 2.8 to 77.3 +/- 2.6 kg (p < 0.05). Circulating concentrations of NT and sICAM-1 were significantly reduced with treatment (approximately 25% and approximately 10%, respectively), whereas sPLA2 levels were significantly elevated (approximately 45%). Elevations in sPLA2 were negatively correlated with changes in NT (r = -0.58, p = 0.047); reductions in NT did not correlate significantly with reductions in sICAM-1. It appears that circulating markers of endothelial health are susceptible to short-term exercise interventions with modest reduction in body mass, and such a lifestyle modification may improve endothelial health by reducing protein nitration products and cellular adhesion.
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PMID:Short-term lifestyle modification alters circulating biomarkers of endothelial health in sedentary, overweight adults. 1711 Oct 5


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