Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors evaluated the frequency and type of lipid disorders associated with subclinical hypothyroidism (SH) in older women referred to their university vascular disease prevention clinic. They also assessed the results of thyroid replacement therapy. Fasting serum lipid profiles and thyroid function tests were measured in 333 apparently healthy women (mean age: 71.8 +/- 7 years). These women were divided into 3 groups: group I: 60-69 years old (n = 132); group II: 70-79 years old (n = 153); group III: 80-89 years old (n = 48). SH was defined as a serum thyrotropin concentration higher than 3.20 mlU/mL with a normal free thyroxine concentration. The prevalence of SH was 7.5%. Thyrotropin was higher than 3.20 mU/mL in 25 women; 7 (5.3%), 14 (9.2%), and 4 (8.3%) in groups I, II, and III, respectively. Low-density lipoprotein cholesterol (LDL-C) concentrations were higher in the women with SH (p = 0.037). The mean values of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C ratio, lipoprotein (a) (Lp[a]), apolipoprotein A-I (apo AI) apolipoprotein B100 (apo B) and apo B/apo A ratio were higher and triglycerides (TG) were lower, compared with those with normal levels of thyrotropin. However, none of these differences reached significance. Restoration of euthyroid status (thyroxine: 50-100 microg/day) in 17 SH women significantly improved TC (p = 0.017), LDL-C (p = 0.014), TC/HDL-C (p = 0.05), LDL-C/HDL-C (p = 0.03), apo B (p = 0.013), and Lp(a) (p = 0.0005) values. SH is relatively common in older women attending a vascular disease prevention clinic. Thyroid hormone replacement therapy significantly improved serum lipids. In particular, the reduction in LDL-C and Lp(a) concentrations may be of clinical benefit.
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PMID:Subclinical hypothyroidism and lipid abnormalities in older women attending a vascular disease prevention clinic: effect of thyroid replacement therapy. 1456 32

Although oxidatively damaged lipoproteins are implicated in vascular injury, there is little information regarding the role of high-density lipoprotein (HDL) oxidation in atherogenesis. One potential pathway involves hypochlorous acid (HOCl) produced by myeloperoxidase (MPO), a heme protein secreted by phagocytes. We previously showed that 3-chlorotyrosine is a specific product of HOCl. Therefore, to explore the role of oxidized HDL in the pathogenesis of vascular disease, we used MS to quantify 3-chlorotyrosine in HDL isolated from plasma and atherosclerotic tissue. HDL from human aortic atherosclerotic intima had an 8-fold higher level of 3-chlorotyrosine than plasma HDL. Tandem MS analysis identified MPO as a component of lesion HDL, suggesting that the two interact in the artery wall. Moreover, immunohistochemical studies found that specific epitopes derived from HOCl colocalized with apolipoprotein A-I, the major protein of HDL. These observations strongly support the hypothesis that MPO promotes HDL oxidation in the human artery wall. Levels of 3-chlorotyrosine were elevated in HDL isolated from the blood of humans with established coronary artery disease, suggesting that circulating levels of oxidized HDL represent a unique marker for clinically significant atherosclerosis. HDL or lipid-free apolipoprotein A-I exposed to HOCl was less able to remove cholesterol from cultured cells by a pathway requiring the cell membrane transporter ATP-binding cassette transporter A1. The detection of 3-chlorotyrosine in HDL isolated from vascular lesions raises the possibility that MPO, by virtue of its ability to form HOCl, may promote atherogenesis by counteracting the established antiatherogenic effects of HDL and the ATP-binding cassette transporter A1 pathway.
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PMID:The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. 1532 14

It has been suggested that ABCA1 interacts preferentially with lipid-poor apolipoprotein A-I (apoA-I). Here, we show that treatment of plasma with dimyristoyl phosphatidylcholine (DMPC) multilamellar vesicles generates prebeta(1)-apoA-I-containing lipoproteins (LpA-I)-like particles similar to those of native plasma. Isolated prebeta(1)-LpA-I-like particles inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than HDL(3) (IC(50) = 2.20 +/- 0.35 vs. 37.60 +/- 4.78 microg/ml). We next investigated the ability of DMPC-treated plasma to promote phospholipid and unesterified (free) cholesterol efflux from J774 macrophages stimulated or not with cAMP. At 2 mg DMPC/ml plasma, both phospholipid and free cholesterol efflux were increased ( approximately 50% and 40%, respectively) in cAMP-stimulated cells compared with unstimulated cells. Similarly, both phospholipid and free cholesterol efflux to either isolated native prebeta(1)-LpA-I and prebeta(1)-LpA-I-like particles were increased significantly in stimulated cells. Furthermore, glyburide significantly inhibited phospholipid and free cholesterol efflux to DMPC-treated plasma. Removal of apoA-I-containing lipoproteins from normolipidemic plasma drastically reduced free cholesterol efflux mediated by DMPC-treated plasma. Finally, treatment of Tangier disease plasma with DMPC affected the amount of neither prebeta(1)-LpA-I nor free cholesterol efflux. These results indicate that DMPC enrichment of normal plasma resulted in the redistribution of apoA-I from alpha-HDL to prebeta-HDL, allowing for more efficient ABCA1-mediated cellular lipid release. Increasing the plasma prebeta(1)-LpA-I level by either pharmacological agents or direct infusions might prevent foam cell formation and reduce atherosclerotic vascular disease.
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PMID:Structural modification of plasma HDL by phospholipids promotes efficient ABCA1-mediated cholesterol release. 1565 21

Carbonyl stress is implicated in accelerated vascular disease, but little is known about the factors that control the reactions of carbonyls with proteins. Acrolein is a reactive carbonyl generated by the oxidation of lipids and amino acids. It also forms during cigarette smoking. We therefore investigated the possibility that acrolein might react with apolipoprotein A-I (apoA-I), the major protein of high-density lipoprotein (HDL), which plays a critical role in mobilizing cholesterol from artery wall macrophages. Tandem mass spectrometric analysis demonstrated that lysine residues were the only amino acids in apoA-I that were modified by acrolein. Immunohistochemical studies with a monoclonal antibody revealed that acrolein adducts colocalized with apoA-I in human atherosclerotic lesions. Moreover, the ability of apoA-I to remove cholesterol from cultured cells was impaired after exposure to acrolein, suggesting that the carbonyl might interfere with apoA-I's normal function of promoting cholesterol efflux from artery wall cells. Our observations suggest that acrolein may interfere with normal HDL cholesterol transport by modifying apoA-I. This structural damage might play a critical role in atherogenesis by impairing cholesterol removal from artery wall cells.
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PMID:Acrolein modifies apolipoprotein A-I in the human artery wall. 1603 61

Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr(-/-)) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr(-/-) mice and Ldlr(-/-)/apoA-I null (apoA-I(-/-)), double-knockout mice. Ldlr(-/-) and Ldlr(-/-)/apoA-I(-/-) mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium- and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr(-/-) mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium- and eNOS-dependent vasodilation in Ldlr(-/-)/apoA-I(-/-) mice but did not reduce wall thickness as it had in Ldlr(-/-) mice. Vascular endothelial cells were treated with 22(R)-hydroxycholesterol with and without L-4F. 22(R)-Hydroxycholesterol decreased NO (*NO) and increased superoxide anion (O2*-) production and increased ATP-binding cassette transporter-1 and collagen expression. L-4F restored *NO and O2*- balance, had little effect on ATP-binding cassette transporter-1 expression, but reduced collagen expression. These data demonstrate that although D-4F restores vascular endothelial cell and eNOS function to increase vasodilation, HDL containing apoA-I, or at least some critical concentration of the antiatherogenic lipoprotein, is required for D-4F to decrease vessel wall thickness.
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PMID:Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet. 1630 51

No evidence of premature vascular disease is found in apolipoprotein A-I(Milano) (apoA-I(M)) human carriers, despite very low high density lipoprotein (HDL) cholesterol levels. Whether apoA-I(M) may impart a "gain of function" in atherosclerosis protection compared to wild-type apoA-I is hotly debated. To address this question, knock-in mice expressing human apoA-I or apoA-I(M) were crossed with atherosclerosis-susceptible mice expressing the human apoB/A-II transgene (h-B/A-II/A-I(Hu/Hu) and h-B/A-II/A-I(M)(Hu/Hu)). On a chow diet, h-B/A-II/A-I(M)(Hu/Hu) mice were characterized by low HDL cholesterol levels compared to h-B/A-II/A-I(Hu/Hu) mice (35.65+/-8.00 mg/dl versus 58.09+/-13.50mg/dl, respectively; p<0.005). Gender differences in response to high fat diet were observed in both h-B/A-II/A-I(M)(Hu/Hu) and h-B/A-II/A-I(Hu/Hu) lines. h-B/A-II/A-I(M)(Hu/Hu) females had higher total cholesterol levels compared to h-B/A-II/A-I(Hu/Hu) females (895.08+/-183.07 mg/dl versus 544.43+/-116.42 mg/dl; p<0.05) and developed larger atherosclerotic lesions (148,260+/-78,924 microm(2) versus 54,132+/-43,204 microm(2), respectively; p<0.05). On the contrary, no difference in mean lesion area was found between h-B/A-II/A-I(M)(Hu/Hu) and h-B/A-II/A-I(Hu/Hu) males (19,779+/-6,098 microm(2) versus 15,706+/-13,095 microm(2); p=0.685). Our data suggest that, in the atherosclerosis-susceptible human apoB/A-II mouse model, expression of the human apoA-I(M) gene does not have protective advantage over that of the apoA-I gene.
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PMID:Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model. 1628 90

Atherothrombotic vascular disease continues to be a leading cause of morbidity and mortality in much of the world. Although a healthy lifestyle and low-density lipoprotein cholesterol lowering significantly reduce cardiovascular morbidity and mortality, substantial number of adverse vasoocclusive events continue to occur. These realities have brought attention to additional therapies that could further reduce cardiovascular events. High-density lipoprotein (HDL)/apolipoprotein A-I (apo A-I)-based therapies are a potential therapeutic strategy against atherothrombotic vascular disease because of the known inverse relationship between HDL cholesterol and coronary heart disease, favorable and pleotrophic biologic effects of HDL/apo A-I, results of preclinical experimental studies, and emerging proof of concept in clinical studies. A variety of HDL/apo A-I-based therapies are currently under investigation, including synthetic peptides that mimic the function of HDL. Such apo A-I mimetic peptides are the focus of this review.
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PMID:Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management. 1629 66

Vascular disease risk is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL provides vascular protection are unclear. The disruption of endothelial monolayer integrity is an important contributing factor in multiple vascular disorders, and vascular lesion severity is tempered by enhanced endothelial repair. Here, we show that HDL stimulates endothelial cell migration in vitro in a nitric oxide-independent manner via scavenger receptor B type I (SR-BI)-mediated activation of Rac GTPase. This process does not require HDL cargo molecules, and it is dependent on the activation of Src kinases, phosphatidylinositol 3-kinase, and p44/42 mitogen-activated protein kinases. Rapid initial stimulation of lamellipodia formation by HDL via SR-BI, Src kinases, and Rac is also demonstrable. Paralleling the in vitro findings, carotid artery reendothelialization after perivascular electric injury is blunted in apolipoprotein A-I(-/-) mice, and reconstitution of apolipoprotein A-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI(-/-) mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated signaling, and these mechanisms promote endothelial monolayer integrity in vivo.
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PMID:High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. 1633 87

Epidemiologic and experimental observations suggest high density lipoprotein (HDL) has a protective effect against atherothrombotic vascular disease. These findings have stimulated considerable interest to promote HDL as a potential therapeutic strategy. Several exciting therapeutic strategies have recently emerged and currently are the focus of intense research interest. One approach is the direct administration of HDL or its components such as apolipoprotein A-I (apoA-I). Recently, much attention has focused on a naturally occurring variant of apoA-I, apoA-I(Milano) (apoA-IM) characterized by a cysteine for arginine substitution that is associated with low rates of vascular disease and significant longevity in its carriers, despite markedly reduced HDL and elevated triglyceride levels. The mutation alters the characteristics of the protein resulting in apoA-IM being functionally more effective than normal apoA-I. A number of animal and laboratory studies have demonstrated significant antiatherogenic, antiproliferative, antirestenotic, antiplatelet, antithrombotic, antiinflammatory, and antioxidant properties of apoA-IM. Furthermore, apoA-IM has been shown to promote reverse cholesterol transport, improve endothelial dysfunction and induce rapid mobilization of tissue cholesterol resulting in regression and alteration of plaque composition in animal models of atherosclerosis. Recently, a pilot clinical trial of recombinant apoA-IM demonstrated significant and rapid regression of atherosclerosis as measured by intravascular ultrasound in patients with acute coronary syndromes. These promising data provide the rationale for the development of reconstituted HDL utilizing recombinant apoA-IM as a potential therapeutic approach for atherothrombotic vascular disease in humans.
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PMID:ApoA-I Milano/phospholipid complexes emerging pharmacological strategies and medications for the prevention of atherosclerotic plaque progression. 1650 67

Migrant and native South Asians appear to be at increased risk of Type II diabetes mellitus and coronary disease. The aim of the present study was to determine the relationship between the most accurate summary index of the lipoprotein-related risk of vascular disease, the apoB (apolipoprotein B-100)/apoA-I (apolipoprotein A-I) ratio, and body composition in established migrant South Asians and white Caucasians living in Canada. Men and women living in Montreal, Canada between the ages of 20-60 years were recruited for participation in the study. Subjects were excluded if they had a history of cardiovascular disease or were taking lipid-lowering medication. Individuals identified themselves as Asian Indian or Caucasian. Anthropometric measurements were collected, including weight, height, waist circumference, hip circumference and body fat percentage. Plasma samples were analysed for total cholesterol, HDL-C (high-density lipoprotein-cholesterol), apoA-I and apoB. Indian subjects had a substantially higher WHR (waist-to-hip ratio) than Caucasian subjects [men, 0.93+/-0.01 compared with 0.86+/-0.01 respectively (P<0.001); women, 0.88+/-0.01 compared with 0.77+/-0.01 respectively (P<0.0001)]. WHR correlated strongly with body fat percentage in Caucasians (men, r=0.63, P=0.0002; women, r=0.74, P<0.0001). By contrast, there was no correlation in Indians (men, r=0.22, P value not significant; women, r=0.23, P value not significant). In addition, Indian men and women had a higher apoB/A-I ratio than Caucasians [men, 0.85+/-0.04 compared with 0.66+/-0.04 respectively (P=0.001); women, 0.73+/-0.04 compared with 0.56+/-0.03 respectively (P=0.0003)]. Of interest, there were also significant correlations between the apoB/apoA-I ratio and WHR in all of the groups, except the Indian women, which were stronger than the correlation of the apoB/apoA-I ratio with BMI. On the other hand, there was no significant relationship between the apoB/apoA-I ratio and the body fat percentage in any of the groups. In conclusion, the present study confirms that, as body fat percentage increases, the distribution of body fat differs between migrant Indians and Caucasians living in Canada. It also relates differences in body fat distribution to differences in the apoB/apoA-I ratio, providing at least part of the answer as to why South Asians may be at increased risk of vascular disease.
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PMID:Body composition and the apoB/apoA-I ratio in migrant Asian Indians and white Caucasians in Canada. 1671 24


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