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)

Platelets are involved in the development of atherothrombosis. However, the anti-atherosclerotic effects of thienopiridines have not been, as yet, proven. We analyzed the effects of ticlopidine on atherogenesis in apolipoprotein E/low density lipoprotein receptor double knockout (apoE/LDLR(-/-)) mice. 2-month-old apoE/LDLR(-/-) mice fed a Western diet (21% fat, 0.15% cholesterol) were treated with ticlopidine (90 mg/kg/day) for a period of 4 months. In 6-month-old apoE/LDLR(-/-) mice treated with ticlopidine and in their non-treated counterparts we analyzed: cholesterol and triglyceride levels, the size of atherosclerotic plaques in aortic roots (oil red-O staining, cross-section method), and in the whole aorta (Sudan IV staining, en face method), the number of macrophages in atherosclerotic plaque (CD68 staining), as well as the endothelial function in the isolated thoracic aorta. Concentrations of total cholesterol and triglycerides in plasma were not altered by treatment with ticlopidine. However, the size of atherosclerotic plaques measured in aortic roots by the cross-section method and the number of macrophages estimated by anti-CD68 staining were significantly reduced by ticlopidine treatment. In contrast, the effect of ticlopidine on the area covered by plaques in the whole aorta (en face analysis) was not statistically significant. Importantly, acetylcholine-induced vasodilation in isolated aorta was improved in ticlopidine-treated apoE/LDLR(-/-) mice as compared to their non-treated counterparts. In conclusion, ticlopidine attenuates the progression of atherosclerosis and improves the endothelial function in apoE/LDLR(-/-) mice.
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PMID:Ticlopidine attenuates progression of atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice. 1717 98

Male cynomolgus macaques (n=91) consumed an isoflavone (IF)-free, atherogenic control diet containing casein/lactalbumin for 5 months, then were randomized to three groups: control (n=30) continued on the control diet; low IF (n=30) received a mixture of unmodified and IF-depleted soy protein isolate (SPI) (0.94 mg IF/g protein, approximating a human intake of 75 mg/day); high IF (n=31) received unmodified SPI (1.88 mg IF/g protein, approximating a human intake of 150 mg/day) for 31 months. Iliac and carotid artery atherosclerosis, and arterial and hepatic mRNA transcripts related to inflammation and estrogen receptors (ER) were measured. Trend analysis identified a significant inverse relationship between dietary IF content and plaque area in the iliac (p<0.05) but not carotid arteries (p>0.13). No significant effect of diet on inflammatory gene or estrogen receptor expression was observed. Plaque area was positively correlated with the mRNA transcript levels for arterial MCP-1, ICAM-1, and the macrophage marker CD68 (all r>0.25, p<0.03), and negatively correlated with ER alpha and ER beta (all r<-0.23, p<0.03). Coronary artery plaque area appeared to be more closely associated with gene expression patterns of the iliac arteries than the carotid arteries. The data suggests benefits of dietary soy on atherosclerotic plaque development in males may be mediated through inflammation-independent pathways. The negative associations of arterial ER alpha expression with atherosclerosis lend support to a mechanistic role for estrogen receptors in atherosclerosis susceptibility which merits further study.
Atherosclerosis 2008 Jan
PMID:Effects of dietary soy protein on iliac and carotid artery atherosclerosis and gene expression in male monkeys. 1736 95

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs), such as lectin-like ox-LDL receptor-1 (LOX-1), is a key event in atherosclerosis. In the present study, we used differentiated Caco-2 cells as a model of the human small intestine to evaluate the suppressive effects of 16 traditional food items selected from Okinawa on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced LOX-1 mRNA expression in THP-1 human monocyte-like cells. Three Zingiberaceae plants, Curcuma aromatica Salisbury, Curcuma longa L., and Zingiber zerumbet Smith, markedly suppressed that expression. When added to the apical sides of Caco-2 monolayers, zerumbone, a sesquiterpene from Z. zerumbet Smith, was found to permeate into the basolateral medium as an intact structure in a time-dependent manner. alpha-Humulene, a structural analog of zerumbone lacking the alpha,beta-unsaturated carbonyl group, did not suppress LOX-1 mRNA expression, indicating that its electrophilic moiety might play pivotal roles in its activities. Further, zerumbone attenuated the expression of SR-A, SR-PSOX, and CD36, but not that of CD68 or CLA-1, leading to a blockade of DiI-acLDL uptake, while it also inhibited the transcriptional activities of activator protein-1 and nuclear factor-kappaB. Together, our results indicate that zerumbone is a potential phytochemical for regulating atherosclerosis with reasonable action mechanisms.
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PMID:Zerumbone suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. 1742 Jun 7

Systemic infections can trigger heart attacks. We conducted an autopsy study to investigate the pathologic effect of systemic infections on coronary artery inflammation. We studied 14 atherosclerotic patients diagnosed with an acute systemic infection. Our control group (n=13) had atherosclerosis without infection. The groups were similar in luminal stenosis and age. Coronary artery sections were stained with H&E and markers for macrophages (CD68), T cells (CD3), and dendritic cells (S100). On pathologic examination, 5 infected patients had acute myocardial infarction with thrombosis. Macrophage density in plaques and in periadventitial fat was higher in the infected group (NS). The infected patients' adventitia had significantly more macrophages (1,577 +/- 1,872 vs 265 +/- 185 per mm(2); P=0.047). The macrophage density, similar in the control group's adventitia and plaque, was significantly greater in the infected group's adventitia than in the plaque. The adventitia and periadventitial fat of the infected group had more T cells than did samples from the control group (48.4 +/- 45.0 vs 14.1 +/- 6.3 per mm(2); P=0.002). The groups exhibited similar plaque T-cell density. The infected patients' plaques, but not the adventitia and periadventitial fat, had more dendritic cells than did the controls' (3.2 +/- 2.5 vs 0.3 +/- 0.5 per mm(2); P=0.022). To our knowledge, this is the 1st report to establish a connection between acute systemic infections and significant increases in inflammatory cells in the atherosclerotic coronary arteries of human beings. This offers a new therapeutic target for preventing heart attacks in high-risk patients.
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PMID:Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. 1742 Jul 87

Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61+/-2% of aorta in the LDLR KO mice, but only 36+/-3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappaB and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.
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PMID:Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. 1755 64

Sclerotic calcification of the aortic valve is a common disease in advanced age. Its pathophysiology is unclear. However, pathobiological similarities to atherosclerosis have been shown in several studies. The current study assesses gene profiling of severe calcified stenotic human aortic valves identifying transforming growth factor (TGF)-beta, Eotaxin3, vascular adhesion protein-1 (VAP-1) and monokine induced by interferon-gamma (MIG) as potential atherosclerotic target genes in severe calcified and stenotic aortic valves, and analyzes the effects of statins on their expression as part of an anti-inflammatory treatment strategy. We collected human severe calcified and stenotic aortic valves with (CSAV+) or without (CSAV-) statin pre-treatment prior to valve replacement and investigated gene profiling by using micro-array technique and real-time PCR for the TGF-beta, Eotaxin3, VAP-1 and MIG expression. In comparison to atherosclerotic plaques of carotid arteries, immunohistochemical staining was investigated. Results were contrasted to human normal non-calcified aortic valves as controls (C). As compared to C, TGF-beta, Eotaxin3, MIG or VAP-1 was significantly upregulated in CSAV-. In CSAV+ no significant change in gene expression was found for Eotaxin3 and MIG. In contrast, VAP-1 and TGF-beta were still upregulated. Corresponding gene expression was confirmed on atherosclerotic plaque formations of carotid arteries. Monocyte/Macrophage infiltration (presence of CD68) on aortic valves (CSAV+, CSAV-, or C) confirmed inflammatory nature of the disease. Our data support further evidence for atherosclerotic inflammation as a trigger for sclerosis in end-stage calcified stenotic aortic valves by showing upregulation of gene expression for TGF-beta, VAP-1, MIG and Eotaxin3, which is only partially inhibited by previous statin therapy. Potent benefits of statin treatment on early stages of valve disease are still propagated.
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PMID:VAP-1, Eotaxin3 and MIG as potential atherosclerotic triggers of severe calcified and stenotic human aortic valves: effects of statins. 1749 Jun 41

Endothelial lipase (EL) is expressed in endothelial cells, and affects plasma lipoprotein metabolism by hydrolyzing phospholipids in HDL. To determine the cellular expression of EL mRNA and protein in human atherosclerotic lesions, we performed in situ hybridization and immunohistochemical studies on sections of carotid endarterectomy specimens from patients with symptomatic cerebrovascular disease. In each of eight patients, EL mRNA and/or protein were seen in areas between the necrotic core and the fibrotic cap where they colocalized with LPL and macrophage-specific CD68. Moreover, there was a positive association between the expression of EL mRNA and CD68 mRNA in plaques from 26 patients. The impact of differentiation from monocytes into macrophages, and subsequently foam cells (by incubation with acetylated LDL) on expression was studied using THP-1 monocytes and primary human monocytes. EL mRNA expression increased markedly when either type of monocytes was differentiated into macrophages. Upon further differentiation into foam cells EL mRNA decreased whereas protein levels remained high compared to monocytes. In conclusion, macrophages in advanced human atherosclerotic lesions display high levels of EL expression, and the level of EL expression varies greatly during transformation of blood monocytes into foam cells.
Atherosclerosis 2007 Dec
PMID:Endothelial lipase is highly expressed in macrophages in advanced human atherosclerotic lesions. 1757 Mar 72

Monocyte adhesion to arterial endothelial cells is the initial step in atherosclerosis. Whereas angiotensin II is known to elicit leukocyte adhesion, it is not clear whether blockade of the angiotensin II receptor signaling reduces monocyte adhesion to endothelial cells beyond its antihypertensive action. This study compared the effect of two different antihypertensive drugs on monocyte adhesion to thoracic aorta endothelium in spontaneously hypertensive rats (SHR): the angiotensin II receptor blocker, valsartan (20 mg . kg(-1) . day(-1)) and the vasodilator, hydralazine (0.75 mg . kg(-1) . day(-1)). The effects were quantitated in vivo using an enface method that optimizes the observation of endothelial surfaces after immunohistochemical staining for CD68. Both agents significantly and comparably reduced blood pressure over 4-week treatment course. Both valsartan and hydralazine profoundly reduced monocyte adhesion compared with nontreated controls, with valsartan having a modestly more reductive effect. Both agents also reduced the intima and medial thickening with valsartan reducing the mean thickness modestly more than hydralazine. Our data confirms that the reduction of blood pressure is effective method to reduce monocyte adhesion. Also, our date demonstrates that valsartan has a modest beneficial effect on monocyte adhesion to endothelial cells and arterial intima-medial vessel thickening beyond its action as an antihypertensive agent.
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PMID:Angiotensin II type 1 receptor blocker reduces monocyte adhesion to endothelial cells in spontaneously hypertensive rats. 1764 43

Periodontitis increases the atherosclerosis risk, but information on the role of periodontal pathogens in atherogenesis is limited. In the present study we have investigated, whether the major periodontal pathogen, Aggregatibacter (Actinobacillus) actinomycetemcomitans, induces development of atherosclerosis in apolipoprotein E-deficient mice. The mice received 4, 6, or 8 weekly i.v. injections of live pathogen (10(7)CFU/50 microl/mouse) or saline as control, and were killed 1 week after the last injection. The atherosclerotic lesion formation was examined from whole aortas and aortic sinus cryosections after lipid staining. Neither the lesion area in the aortas or en face analyses, nor their immunoreactivity to the macrophage-marker CD68 differed significantly between the infected and the control mice. However, the pathogen administration increased serum C-reactive protein (CRP) concentrations, and induced proatherogenic lipoprotein profiles with smaller particle sizes in very-low density (VLDL), low density (LDL), and high density (HDL) lipoprotein fractions. It also caused elevated matrix metalloproteinase-9 expression in the aortas and increased serum gelatinase level. Lipopolysaccharide deriving from the pathogen was associated with proatherogenic lipoprotein fractions: VLDL and especially LDL. The results indicate that A. actinomycetemcomitans contributes to disturbed lipoprotein profiles, inflammatory reaction, and matrix remodelling which are known to promote the development of atherosclerosis.
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PMID:Aggregatibacter actinomycetemcomitans induces MMP-9 expression and proatherogenic lipoprotein profile in apoE-deficient mice. 1788 99

LDL receptor-null (LDLR(-/-)) mice on a Western diet (WD) develop endothelial dysfunction and atherosclerosis, which are improved by the apolipoprotein A-I (apoA-I) mimetic peptide D-4F. Focusing on the kidney, LDLR(-/-)mice were fed a WD with D-4F or the inactive control peptide scrambled D-4F (ScD-4F) added to their drinking water. The control mice (ScD-4F) developed glomerular changes, increased immunostaining for MCP-1/CCL2 chemokine, increased macrophage CD68 and F4/80 antigens, and increased oxidized phospholipids recognized by the EO6 monoclonal antibody in both glomerular and tublo-interstitial areas. All of these parameters were significantly reduced by D-4F treatment, approaching levels found in wild-type C57BL/6J or LDLR(-/-) mice fed a chow diet. Sterol-regulatory element binding protein-1c (SREBP-1c) mRNA levels and triglyceride levels were elevated in the kidneys of the control mice (ScD-4F) fed the WD compared with C57BL/6J and LDLR(-/-) mice on chow (P < 0.001 and P < 0.001, respectively) and compared with D-4F-treated mice on the WD (P < 0.01). There was no significant difference in plasma lipids, lipoproteins, glucose, blood pressure, or renal apoB levels between D-4F- and ScD-4F-treated mice. We conclude that D-4F reduced renal oxidized phospholipids, resulting in lower expression of SREBP-1c, which, in turn, resulted in lower triglyceride content and reduced renal inflammation.
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PMID:D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet. 1792 50


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