Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

ATP binding cassette transporter A1 (ABCA1) mediates the cellular efflux of phospholipids and cholesterol to lipid-poor apolipoprotein A1 (apoA1) and plays a significant role in high density lipoprotein (HDL) metabolism. ABCA1's role in the causation of Tangier disease, characterized by absent HDL and premature atherosclerosis, has implicated this transporter and its regulators liver-X-receptoralpha (LXRalpha) and peroxisome proliferator activated receptorgamma (PPARgamma) as new candidates potentially influencing the progression of atherosclerosis. In addition to lipid regulation, these genes are involved in apoptosis and inflammation, processes thought to be central to atherosclerotic plaque progression. A Medline-based review of the literature was carried out. Tangier disease and human heterozygotes with ABCA1 mutations provide good evidence that ABCA1 is a major candidate influencing atherosclerosis. Animal and in vitro experiments suggest that ABCA1 not only mediates cholesterol and phospholipid efflux, but is also involved in the regulation of apoptosis and inflammation. The complex and beneficial interactions between apoA1 and ABCA1 seem to be pivotal for cholesterol efflux. The expression of the ABCA1 is tightly regulated. Furthermore the plaque microenvironment could potentially promote ABCA1 protein degradation thus compromising cholesterol efflux. PPAR-LXR-ABCA1 interactions are integral to cholesterol homeostasis and these nuclear receptors have proven anti-inflammatory and anti-matrix metalloproteinase activity. Therapeutic manipulation of the ABCA1 transporter is feasible using PPAR and LXR agonists. PPAR agonists like glitazones and ABCA1 protein stabilization could potentially modify the clinical progression of atherosclerotic lesions.
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PMID:ABCA1 and atherosclerosis. 1601 95

Cholesterol is a major component of atherosclerotic plaques. Cholesterol accumulation within the arterial intima and atherosclerotic plaques is determined by the difference of cellular cholesterol synthesis and/or influx from apo B-containing lipoproteins and cholesterol efflux. In humans, apo A-1 Milano infusion has led to rapid regression of atherosclerosis in coronary arteries. We hypothesised that a multifunctional plasma delipidation process (PDP) would lead to rapid regression of experimental atherosclerosis and probably impact on adipose tissue lipids. In hyperlipidemic animals, the plasma concentrations of cholesterol, triglyceride and phospholipid were, respectively, 6-, 157-, and 18-fold higher than control animals, which consequently resulted in atherosclerosis. PDP consisted of delipidation of plasma with a mixture of butanol-diisopropyl ether (DIPE). PDP removed considerably more lipid from the hyperlipidemic animals than in normolipidemic animals. PDP treatment of hyperlipidemic animals markedly reduced intensity of lipid staining materials in the arterial wall and led to dramatic reduction of lipid in the adipose tissue. Five PDP treatments increased apolipoprotein A1 concentrations in all animals. Biochemical and hematological parameters were unaffected during PDP treatment. These results show that five PDP treatments led to marked reduction in avian atherosclerosis and removal of lipid from adipose tissue. PDP is a highly effective method for rapid regression of atherosclerosis.
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PMID:Plasma delipidation process induces rapid regression of atherosclerosis and mobilisation of adipose tissue. 1604 67

The authors evaluated the lipid profile of children with a positive family history of coronary heart disease (CHD), cerebrovascular disease (CVD), or hyperlipidemia and compared them with controls in order to identify risk indicators for atherosclerosis. A group of 315 children (group A) aged more than 2 years old with a positive family history were evaluated for serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B100 (ApoB100), apolipoprotein A1 (Apo A1), and lipoprotein (a) (Lp[a]). These values were compared with the levels of a control group of 214 children of comparable age (group B). The median age of children in groups A and B was 10.6 (range 2.3-16) and 9.8 (range 3-13.7) years of age, respectively. Among these children, 196 (52%), 47 (12.5%), and 72 (19.1%) had a positive family history of CHD (group A1), cerebrovascular disease (CVD) (group A2), and hypercholesterolemia (group A3), respectively. We identified 8 children with genetically determined dyslipidemia: 2 children with homozygous and 6 with heterozygous familial hypercholesterolemia. Children in group A3 had significantly higher concentrations of TC, TG, LDL-C, and ApoB100 and lower concentrations of Apo A1 compared with controls, while no significant differences were found in concentrations of lipid variables among children of group A1, A2, and A3. Significant differences were also noted in the concentrations of TC, LDL-C, and Lp(a) between children of group A1 and controls. Screening the progeny of young patients with CHD or familial hypercholesterolemia can identify children at excessive risk for future vascular disease.
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PMID:Lipid profile of children with a family history of coronary heart disease or hyperlipidemia: 9-year experience of an outpatient clinic for the prevention of cardiovascular diseases. 1607 21

Serum lipids increase during pregnancy. However, data are scarce for lipid changes in pregnant women with heterozygous familiar hypercholesterolemia (FH). The purpose of the present study was to examine plasma lipids and lipoproteins during pregnancy in women with FH. In 22 pregnant women blood samples were collected at gestational weeks 17-20 (baseline), 24, 30 and 36. Total- and LDL cholesterol increased significantly between baseline and gestational week 36 by 29% and 30%, respectively, compared to 25% and 34% in a reference group of 149 healthy pregnant women. Notably, the plasma lipid concentrations in the FH women were much higher than in the reference women. Triglycerides increased (P<0.05) by 116% and 103%, in the FH group and reference group, respectively. HDL cholesterol was unchanged in both groups. Moreover, apolipoprotein B increased significantly during pregnancy in the FH women, whereas apolipoprotein A1 and lipoprotein (a) were unchanged. Pregnancy outcomes in the FH group did not differ significantly from those in the reference group. In conclusion, the relative increase in plasma lipids was similar in pregnant women with FH and in healthy women, but the absolute magnitude was considerably larger in pregnant FH women.
Atherosclerosis 2006 Dec
PMID:Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. 1646 29

The role of transmembrane lipidtransporter molecules in the atherosclerotic process. The protective effect of high-density lipoprotein in the atherosclerotic process has been mainly attributed to its role in reverse cholesterol transport. Identification of mutations in the ATP-bindig casette transporter-A1 (ABCA1) as the genetic defect in genetic high-density lipoprotein-deficiency (Tangier disease) and selected patients with familiar hypoalphalipoproteinemia has generated interest in discovering the role of this lipid transporter molecule in the reverse cholesterol transport. It is well established, that the ABCA1 mediates cellular cholesterol efflux through transfer of phospholipids and cholesterol from the inner to the outer layer of the cell membrane, thus enabling the bindig to apolipoproteins. Previous studies showed that the ABCA1 is critically involved in cellular trafficking of cholesterol and phospholipids in total body of lipid homeostasis. In Tangier disease, the loss of the function of ABCA1, leads to an impaired formation of nascent high-density lipoprotein particles by preventing the release of cellular phospholipids and cholesterol to the acceptor apolipoprotein A1. This rare genetic disorder is characterized by a severe high-density lipoprotein deficiency, cholesterol deposition in macrophages and premature atherosclerosis. These findings implicate the ABCA1 as an important therapeutic target for preventing diseases that are associated with accelerated atherogenesis. The present review summarizes the current knowledge of the ABCA1, its pivotal role in the cholesterol homeostasis and preventing atherosclerosis.
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PMID:[The role of transmembrane lipidtransporter molecules in the atherosclerotic process]. 1661 Jun 15

We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS(-/-)/apoE(-/-) mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS(-/-)/apoE(-/-) mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS(-/-)/apoE(-/-) mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE(-/-)/CBS(-/-) mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS(-/-)/apoE(-/-) mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.
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PMID:Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. 1697 11

Familial combined hyperlipidemia (FCHL) constitutes a substantial risk factor for atherosclerosis since it is observed in about 20% of coronary heart disease (CHD) patients under 60 years. FCHL, characterized by elevated levels of total cholesterol (TC) and triglycerides (TGs), or both, is also one of the most common familial hyperlipidemias with a prevalence of 1%-6% in Western populations. Numerous studies have been performed to identify genes contributing to FCHL. The recent linkage and association studies and their replications are beginning to elucidate the genetic variations underlying the susceptibility to FCHL. Three chromosomal regions on 1q21-23, 11p and 16q22-24.1 have been replicated in different study samples, offering targets for gene hunting. In addition, several candidate gene studies have replicated the influence of the lipoprotein lipase (LPL) gene and apolipoprotein A1/C3/A4/A5 (APOA1/C3/A4/A5) gene cluster in FCHL. Recently, the linked region on chromosome 1q21 was successfully fine-mapped and the upstream transcription factor 1 (USF1) gene identified as the underlying gene for FCHL. This finding has now been replicated in independent FCHL samples. However, the total number of variants, the risk related to each variant and their relative contributions to the disease susceptibility are not known yet.
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PMID:Unraveling the complex genetics of familial combined hyperlipidemia. 1693 3

The anti-inflammatory effects of high-density lipoproteins (HDL) are well documented and include inhibition of low-density lipoprotein (LDL) oxidation, reduction of inflammatory cytokines and vascular leukocyte adhesion molecules, and participation in innate immunity. However, certain conditions, including coronary disease, diabetes mellitus, systemic inflammation, and a diet high in saturated fat, are associated with modification of HDL such that it paradoxically enhances LDL oxidation and/or vascular inflammation. Treatment with statins and/or apolipoprotein A1 mimetic peptides improves HDL's anti-inflammatory functions, and these as well as other medications may represent a novel pathway through which to target atherosclerosis.
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PMID:Modifying the anti-inflammatory effects of high-density lipoprotein. 1716 48

The cardioprotective function of high-density lipoprotein (HDL) is largely attributed to its ability to facilitate transport of cholesterol from peripheral tissues to the liver. However, HDL may become dysfunctional through oxidative modification, impairing cellular cholesterol efflux. Here we report a refined molecular model of nascent discoidal HDL, determined using hydrogen-deuterium exchange mass spectrometry. The model reveals two apolipoprotein A1 (apoA1) molecules arranged in an antiparallel double-belt structure, with residues 159-180 of each apoA1 forming a protruding solvent-exposed loop. We further show that this loop, including Tyr166, a preferred target for site-specific oxidative modification within atheroma, directly interacts with and activates lecithin cholesterol acyl transferase. These studies identify previously uncharacterized structural features of apoA1 in discoidal HDL that are crucial for particle maturation, and elucidate a structural and molecular mechanism for generating a dysfunctional form of HDL in atherosclerosis.
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PMID:The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction. 1767 61

Previous studies of leptin with cardiovascular disease (CVD) risk factors have been limited by clinical samples or lack of representation of the general population. This cross-sectional study, designed to examine whether leptin or insulin may mediate the endogenous relation of obesity with metabolic, inflammatory, and thrombogenic cardiovascular risk factors, included 522 men and 514 women aged >or=40 years who completed a physical examination during the third National Health and Nutrition Examination Survey. Participants were free of existing CVD, cancer (except non-melanoma skin cancer), diabetes, or respiratory disease. In multivariable analyses adjusted for race/ethnicity and lifestyle factors, waist circumference (WC) was positively associated with blood pressure, triglyceride, LDL cholesterol, total cholesterol:HDL ratio, apolipoprotein B, C-reactive protein (CRP), and fibrinogen concentrations, and negatively associated with HDL cholesterol and apolipoprotein A1 levels. The associations of WC with the metabolic CVD risk factors were largely attenuated after adjustment for insulin levels, while the associations of WC with the inflammatory and thrombogenic factors (CRP and fibrinogen, respectively) were largely explained by adjustment for leptin concentrations. However, leptin levels were not independently associated with CRP and fibrinogen in men and CRP in women when adjusted for WC. Positive associations of leptin and insulin with fibrinogen in women, independent of WC, were noted. These results suggest that insulin may be an important mediator of the association of obesity with metabolic but not inflammatory or thrombogenic CVD risk factors, while leptin does not appear to influence cardiovascular risk through a shared association with these risk factors. However, we cannot rule out the possibility that leptin and insulin influence cardiovascular risk in women through independent effects on fibrinogen concentrations.
Atherosclerosis 2008 Sep
PMID:The relation of leptin and insulin with obesity-related cardiovascular risk factors in US adults. 1816 70


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