Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000015329.15481.E8
A. Xiang, S. Azen, T. Buchanan, L. Raffel, S. Tan, L. Cheng, Justo Diaz, E. Toscano, M. Quinonnes, Ci-hua Liu, Chi-Hua Liu, L. Castellani, Willa A. Hsueh, J. Rotter, H. Hodis
Although clinical coronary heart disease and many cardiovascular risk factors are well known to aggregate within families, the heritability of carotid artery intima-media thickness (IMT) is less well documented. We report IMT heritability estimates in Mexican American, Salvadoran American, or Guatemalan American (all referred to as Latino) families ascertained through a hypertensive proband. IMT and cardiovascular risk factors (age, sex, blood pressure, body mass index, lipids, fasting glucose, and insulin sensitivity) were measured in 204 adult offspring of 69 hypertensive probands, along with 82 parents (54 probands and 28 spouses). In the offspring, variance component analysis revealed a heritability for IMT of 64% (P < 0.0001) after adjustment for significant cardiovascular risk factors. Genetic factors accounted for 50% of the total variation in IMT, whereas significant cardiovascular risk factors explained 22% (14% were due to age). For offspring and parents combined, adjusted IMT heritability was less, 34% (P =0.0005), with genetic factors accounting for 18% of the total IMT variation, whereas significant cardiovascular risk factors explained 46% (38% were due to age). We conclude that variation in c ommon carotid artery IMT is heritable in Latino families with a hypertensive proband. Heritability is particularly evident in younger family members, suggesting that acquired factors contribute progressively to IMT variability with aging.
{"title":"Heritability of Subclinical Atherosclerosis in Latino Families Ascertained Through a Hypertensive Parent","authors":"A. Xiang, S. Azen, T. Buchanan, L. Raffel, S. Tan, L. Cheng, Justo Diaz, E. Toscano, M. Quinonnes, Ci-hua Liu, Chi-Hua Liu, L. Castellani, Willa A. Hsueh, J. Rotter, H. Hodis","doi":"10.1161/01.ATV.0000015329.15481.E8","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015329.15481.E8","url":null,"abstract":"Although clinical coronary heart disease and many cardiovascular risk factors are well known to aggregate within families, the heritability of carotid artery intima-media thickness (IMT) is less well documented. We report IMT heritability estimates in Mexican American, Salvadoran American, or Guatemalan American (all referred to as Latino) families ascertained through a hypertensive proband. IMT and cardiovascular risk factors (age, sex, blood pressure, body mass index, lipids, fasting glucose, and insulin sensitivity) were measured in 204 adult offspring of 69 hypertensive probands, along with 82 parents (54 probands and 28 spouses). In the offspring, variance component analysis revealed a heritability for IMT of 64% (P < 0.0001) after adjustment for significant cardiovascular risk factors. Genetic factors accounted for 50% of the total variation in IMT, whereas significant cardiovascular risk factors explained 22% (14% were due to age). For offspring and parents combined, adjusted IMT heritability was less, 34% (P =0.0005), with genetic factors accounting for 18% of the total IMT variation, whereas significant cardiovascular risk factors explained 46% (38% were due to age). We conclude that variation in c ommon carotid artery IMT is heritable in Latino families with a hypertensive proband. Heritability is particularly evident in younger family members, suggesting that acquired factors contribute progressively to IMT variability with aging.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77080225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000012282.39306.64
E. Napoleone, A. Di Santo, A. Bastone, G. Peri, A. Mantovani, G. de Gaetano, M. Donati, R. Lorenzet
Inflammation is a major contributing factor to atherosclerotic plaque development and ischemic heart disease. PTX3 is a long pentraxin that was recently found to be increased in patients with acute myocardial infarction. Because tissue factor (TF), the in vivo trigger of blood coagulation, plays a dominant role in thrombus formation after plaque rupture, we tested the possibility that PTX3 could modulate TF expression. Human umbilical vein endothelial cells, incubated with endotoxin (lipopolysaccharide) or the inflammatory cytokines interleukin-1&bgr; and tumor necrosis factor-&agr;, expressed TF. The presence of PTX3 increased TF activity and antigen severalfold in a dose-dependent fashion. PTX3 exerted its effect at the transcription level, inasmuch as the increased levels of TF mRNA, mediated by the stimuli, were enhanced in its presence. The increase in mRNA determined by PTX3 originated from an enhanced nuclear binding activity of the transacting factor c-Rel/p65, which was mediated by the agonists and measured by electrophoretic mobility shift assay. The mechanism underlying the increased c-Rel/p65 activity resided in an enhanced degradation of the c-Rel/p65 inhibitory protein I&kgr;B&agr;. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. Our results suggest that PTX3, by increasing TF expression, potentially plays a role in thrombogenesis and ischemic vascular disease.
{"title":"Long Pentraxin PTX3 Upregulates Tissue Factor Expression in Human Endothelial Cells: A Novel Link Between Vascular Inflammation and Clotting Activation","authors":"E. Napoleone, A. Di Santo, A. Bastone, G. Peri, A. Mantovani, G. de Gaetano, M. Donati, R. Lorenzet","doi":"10.1161/01.ATV.0000012282.39306.64","DOIUrl":"https://doi.org/10.1161/01.ATV.0000012282.39306.64","url":null,"abstract":"Inflammation is a major contributing factor to atherosclerotic plaque development and ischemic heart disease. PTX3 is a long pentraxin that was recently found to be increased in patients with acute myocardial infarction. Because tissue factor (TF), the in vivo trigger of blood coagulation, plays a dominant role in thrombus formation after plaque rupture, we tested the possibility that PTX3 could modulate TF expression. Human umbilical vein endothelial cells, incubated with endotoxin (lipopolysaccharide) or the inflammatory cytokines interleukin-1&bgr; and tumor necrosis factor-&agr;, expressed TF. The presence of PTX3 increased TF activity and antigen severalfold in a dose-dependent fashion. PTX3 exerted its effect at the transcription level, inasmuch as the increased levels of TF mRNA, mediated by the stimuli, were enhanced in its presence. The increase in mRNA determined by PTX3 originated from an enhanced nuclear binding activity of the transacting factor c-Rel/p65, which was mediated by the agonists and measured by electrophoretic mobility shift assay. The mechanism underlying the increased c-Rel/p65 activity resided in an enhanced degradation of the c-Rel/p65 inhibitory protein I&kgr;B&agr;. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. Our results suggest that PTX3, by increasing TF expression, potentially plays a role in thrombogenesis and ischemic vascular disease.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86846989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000014589.22121.6C
S. Lussier‐Cacan, A. Bolduc, M. Xhignesse, T. Niyonsenga, C. Sing
Hyperlipidemia, smoking, and obesity are well-known risk factors for cardiovascular disease. Conversely, moderate alcohol intake is associated with lower atherosclerosis risk. However, the influence of taking alcohol on the interrelationships of these factors in a particular context has not been thoroughly investigated. In this study, we asked whether the association between plasma measures of lipid metabolism and alcohol intake is dependent on context defined by gender, age, body mass index (BMI), smoking, and apolipoprotein E (APOE) genotype. Data were obtained in a sample of 869 women and 824 men who participated in the Quebec Heart Health Survey. There was no evidence that variation among APOE genotypes influenced the association between LDL cholesterol (LDL-C) or HDL cholesterol (HDL)-C and alcohol, after adjustment for age and BMI. Further, the positive (LDL-C and BMI) and the negative (HDL-C and BMI) associations that were observed in men and women with the &egr;3/2 and &egr;3/3 genotypes were not modified by alcohol intake. However, in women with the &egr;4/3 genotype only, we found a significant influence of an alcohol by BMI interaction on the prediction of total cholesterol, LDL-C, HDL-C, apoA-I, and apoB, and this interaction was influenced by the status of smoking. Whereas the influence of an alcohol by BMI interaction on total cholesterol and LDL-C was significant in smokers, its influence on HDL-C was significant only in non-smokers. This study emphasizes the context dependency of the influence of alcohol on lipid metabolism and demonstrates how biological, environmental, and genetic factors interact to determine cardiovascular disease risk.
{"title":"Impact of Alcohol Intake on Measures of Lipid Metabolism Depends on Context Defined by Gender, Body Mass Index, Cigarette Smoking, and Apolipoprotein E Genotype","authors":"S. Lussier‐Cacan, A. Bolduc, M. Xhignesse, T. Niyonsenga, C. Sing","doi":"10.1161/01.ATV.0000014589.22121.6C","DOIUrl":"https://doi.org/10.1161/01.ATV.0000014589.22121.6C","url":null,"abstract":"Hyperlipidemia, smoking, and obesity are well-known risk factors for cardiovascular disease. Conversely, moderate alcohol intake is associated with lower atherosclerosis risk. However, the influence of taking alcohol on the interrelationships of these factors in a particular context has not been thoroughly investigated. In this study, we asked whether the association between plasma measures of lipid metabolism and alcohol intake is dependent on context defined by gender, age, body mass index (BMI), smoking, and apolipoprotein E (APOE) genotype. Data were obtained in a sample of 869 women and 824 men who participated in the Quebec Heart Health Survey. There was no evidence that variation among APOE genotypes influenced the association between LDL cholesterol (LDL-C) or HDL cholesterol (HDL)-C and alcohol, after adjustment for age and BMI. Further, the positive (LDL-C and BMI) and the negative (HDL-C and BMI) associations that were observed in men and women with the &egr;3/2 and &egr;3/3 genotypes were not modified by alcohol intake. However, in women with the &egr;4/3 genotype only, we found a significant influence of an alcohol by BMI interaction on the prediction of total cholesterol, LDL-C, HDL-C, apoA-I, and apoB, and this interaction was influenced by the status of smoking. Whereas the influence of an alcohol by BMI interaction on total cholesterol and LDL-C was significant in smokers, its influence on HDL-C was significant only in non-smokers. This study emphasizes the context dependency of the influence of alcohol on lipid metabolism and demonstrates how biological, environmental, and genetic factors interact to determine cardiovascular disease risk.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85397883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000018287.03856.DD
Xue-qing Wang, Constantinos G. Panousis, M. Alfaro, G. Evans, S. Zuckerman
The pathological role of interferon-&ggr; (IFN-&ggr;) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-&ggr;. In the present study, the pathway by which IFN-&ggr; inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice. IFN-&ggr;–stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN-&ggr; treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN-&ggr; was intact in the Stat1 KO macrophages, inasmuch as IFN-&ggr; was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN-&ggr; on cholesterol efflux and ABC1 expression.
干扰素- ggr的病理作用(IFN-&ggr;)在动脉粥样硬化中的作用是通过对巨噬细胞、泡沫细胞和其他血管细胞的作用介导的。最近，我们报道了通过IFN-&ggr，泡沫细胞中atp结合盒转运体1(ABC1)信息和蛋白水平降低了3- 4倍。在本研究中，IFN-&ggr;用信号转导和转录激活因子(Stat1)敲除小鼠来研究ABC1表达的抑制。IFN-刺激的野生型巨噬细胞衍生的泡沫细胞，如先前报道的那样，表现出胆固醇外流和ABC1表达的减少，以及酰基辅酶a:胆固醇- o -酰基转移酶活性的增加。然而,干扰素-&ggr;Stat1基因敲除小鼠泡沫细胞的处理未能显示出外排或ABC1在信息或蛋白质水平上的表达减少，也没有任何酰基辅酶A:胆固醇- o -酰基转移酶活性的增加。然而，在Stat1敲除小鼠的巨噬细胞中，ABC1 mRNA的表达仍然可以通过乙酰化低密度脂蛋白的脂质负载来证明。最后，IFN-&ggr激活stat1独立基因;在Stat1 KO巨噬细胞中，IFN-&ggr;可以刺激Stat1 KO巨噬细胞中白细胞介素-6产生的增加，这与野生型巨噬细胞中观察到的情况相当。因此，Stat1信号对于IFN-&ggr的抑制作用是必要和充分的;影响胆固醇外排和ABC1表达。
{"title":"Interferon-&ggr;–Mediated Downregulation of Cholesterol Efflux and ABC1 Expression Is by the Stat1 Pathway","authors":"Xue-qing Wang, Constantinos G. Panousis, M. Alfaro, G. Evans, S. Zuckerman","doi":"10.1161/01.ATV.0000018287.03856.DD","DOIUrl":"https://doi.org/10.1161/01.ATV.0000018287.03856.DD","url":null,"abstract":"The pathological role of interferon-&ggr; (IFN-&ggr;) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-&ggr;. In the present study, the pathway by which IFN-&ggr; inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice. IFN-&ggr;–stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN-&ggr; treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN-&ggr; was intact in the Stat1 KO macrophages, inasmuch as IFN-&ggr; was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN-&ggr; on cholesterol efflux and ABC1 expression.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80389312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000013312.32196.49
I. Björkhem, U. Diczfalusy
Oxysterols are oxygenated derivatives of cholesterol that are intermediates or even end products in cholesterol excretion pathways. Because of their ability to pass cell membranes and the blood-brain barrier at a faster rate than cholesterol itself, they are also important as transport forms of cholesterol. In addition, oxysterols have been ascribed a number of important roles in connection with cholesterol turnover, atherosclerosis, apoptosis, necrosis, inflammation, immunosuppression, and the development of gallstones. According to current concepts, oxysterols are physiological mediators in connection with a number of cholesterol-induced metabolic effects. However, most of the evidence for this is still indirect, and there is a discrepancy between the documented potent effects of oxysterols under in vitro conditions and the studies demonstrating that they are of physiological importance in vivo. Oxysterol-binding proteins, such as liver X receptor-&agr; (a nuclear receptor), do have a regulatory role in cholesterol turnover, but the physiological ligand of the protein has not yet been defined with certainty. Recently developed genetically engineered mouse models with markedly reduced or increased concentration of some of the oxysterols have exhibited surprisingly small changes in cholesterol turnover and homeostasis. The present review is a critical evaluation of the literature on oxysterols, in particular, the in vivo evidence for a role of oxysterols as physiological regulators of cholesterol homeostasis and as atherogenic factors.
{"title":"Oxysterols: Friends, Foes, or Just Fellow Passengers?","authors":"I. Björkhem, U. Diczfalusy","doi":"10.1161/01.ATV.0000013312.32196.49","DOIUrl":"https://doi.org/10.1161/01.ATV.0000013312.32196.49","url":null,"abstract":"Oxysterols are oxygenated derivatives of cholesterol that are intermediates or even end products in cholesterol excretion pathways. Because of their ability to pass cell membranes and the blood-brain barrier at a faster rate than cholesterol itself, they are also important as transport forms of cholesterol. In addition, oxysterols have been ascribed a number of important roles in connection with cholesterol turnover, atherosclerosis, apoptosis, necrosis, inflammation, immunosuppression, and the development of gallstones. According to current concepts, oxysterols are physiological mediators in connection with a number of cholesterol-induced metabolic effects. However, most of the evidence for this is still indirect, and there is a discrepancy between the documented potent effects of oxysterols under in vitro conditions and the studies demonstrating that they are of physiological importance in vivo. Oxysterol-binding proteins, such as liver X receptor-&agr; (a nuclear receptor), do have a regulatory role in cholesterol turnover, but the physiological ligand of the protein has not yet been defined with certainty. Recently developed genetically engineered mouse models with markedly reduced or increased concentration of some of the oxysterols have exhibited surprisingly small changes in cholesterol turnover and homeostasis. The present review is a critical evaluation of the literature on oxysterols, in particular, the in vivo evidence for a role of oxysterols as physiological regulators of cholesterol homeostasis and as atherogenic factors.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77613106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000016358.05294.8D
Jianhua Huang, C. Kontos
Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholipid products of PI 3-kinase. In this report, we investigated the hypothesis that overexpression of the tumor suppressor protein PTEN, an inositol phosphatase specific for the products of PI 3-kinase, would inhibit the vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia and restenosis. Effects of PTEN were assessed in primary rabbit VSMCs after overexpression with a recombinant adenovirus and compared with uninfected or control virus-infected cells. PTEN was expressed endogenously in VSMCs, and PTEN overexpression inhibited PDGF-induced phosphorylation of p70s6k, Akt, and glycogen synthase kinase-3-&agr; and -&bgr; but not ERK1 or -2. Overexpression of PTEN significantly inhibited both basal and PDGF-mediated VSMC proliferation and migration, the latter possibly due in part to downregulation of focal adhesion kinase. Moreover, PTEN overexpression induced cleavage of caspase-3 and significantly increased apoptosis compared with control cells. Taken together, these results demonstrate that PTEN overexpression potently inhibits the VSMC responses required for neointimal hyperplasia and restenosis. Adenovirus-expressed PTEN may therefore provide a useful tool for the local treatment of these and other vascular proliferative disorders.
{"title":"Inhibition of Vascular Smooth Muscle Cell Proliferation, Migration, and Survival by the Tumor Suppressor Protein PTEN","authors":"Jianhua Huang, C. Kontos","doi":"10.1161/01.ATV.0000016358.05294.8D","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016358.05294.8D","url":null,"abstract":"Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholipid products of PI 3-kinase. In this report, we investigated the hypothesis that overexpression of the tumor suppressor protein PTEN, an inositol phosphatase specific for the products of PI 3-kinase, would inhibit the vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia and restenosis. Effects of PTEN were assessed in primary rabbit VSMCs after overexpression with a recombinant adenovirus and compared with uninfected or control virus-infected cells. PTEN was expressed endogenously in VSMCs, and PTEN overexpression inhibited PDGF-induced phosphorylation of p70s6k, Akt, and glycogen synthase kinase-3-&agr; and -&bgr; but not ERK1 or -2. Overexpression of PTEN significantly inhibited both basal and PDGF-mediated VSMC proliferation and migration, the latter possibly due in part to downregulation of focal adhesion kinase. Moreover, PTEN overexpression induced cleavage of caspase-3 and significantly increased apoptosis compared with control cells. Taken together, these results demonstrate that PTEN overexpression potently inhibits the VSMC responses required for neointimal hyperplasia and restenosis. Adenovirus-expressed PTEN may therefore provide a useful tool for the local treatment of these and other vascular proliferative disorders.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79825944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000016258.40568.F1
S. Harrap, Kim S Zammit, Z. Wong, F. Williams, M. Bahlo, A. Tonkin, Stanley T Anderson
A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 (P <0.0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 (P <0.005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.
{"title":"Genome-Wide Linkage Analysis of the Acute Coronary Syndrome Suggests a Locus on Chromosome 2","authors":"S. Harrap, Kim S Zammit, Z. Wong, F. Williams, M. Bahlo, A. Tonkin, Stanley T Anderson","doi":"10.1161/01.ATV.0000016258.40568.F1","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016258.40568.F1","url":null,"abstract":"A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 (P <0.0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 (P <0.005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82723430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000016249.96529.B8
I. M. van der Meer, M. D. de Maat, M. Bots, M. Breteler, J. Meijer, A. Kiliaan, A. Hofman, J. Witteman
Inflammatory mediators and soluble cell adhesion molecules predict cardiovascular events. It is not clear whether they reflect the severity of underlying atherosclerotic disease. Within the Rotterdam Study, we investigated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 with noninvasive measures of atherosclerosis. Levels of CRP were assessed in a random sample of 1317 participants, and levels of IL-6 and soluble cell adhesion molecules were assessed in a subsample of 714 participants. In multivariate analyses, logarithmically transformed CRP (regression coefficient [&bgr;]=−0.023, 95% CI −0.033 to −0.012) and IL-6 (&bgr;=−0.025, 95% CI −0.049 to −0.001) were inversely associated with the ankle-arm index. Only CRP was associated with carotid intima-media thickness (&bgr;=0.018, 95% CI 0.010 to 0.027). Compared with the lowest tertile, the odds ratio for moderate to severe carotid plaques associated with levels of CRP in the highest tertile was 2.0 (95% CI 1.3 to 3.0). Soluble intercellular adhesion molecule-1 levels were strongly associated with carotid plaques (odds ratio 2.5, 95% CI 1.5 to 4.4 [highest versus lowest tertile]). Soluble vascular cell adhesion molecule-1 was not significantly associated with any of the measures of atherosclerosis. This study indicates that CRP is associated with the severity of atherosclerosis measured at various sites. Associations of the other markers with atherosclerosis were less consistent.
炎症介质和可溶性细胞粘附分子预测心血管事件。目前尚不清楚它们是否反映了潜在动脉粥样硬化疾病的严重程度。在鹿特丹研究中，我们研究了c反应蛋白(CRP)、白细胞介素-6 (IL-6)、可溶性细胞间粘附分子-1和可溶性血管细胞粘附分子-1与动脉粥样硬化无创测量的关系。在1317名参与者的随机样本中评估CRP水平，在714名参与者的子样本中评估IL-6和可溶性细胞粘附分子的水平。在多变量分析中，对数变换后的CRP(回归系数[&bgr;]= - 0.023, 95% CI [&bgr;]= - 0.033至- 0.012)和IL-6 (&bgr;]= - 0.025, 95% CI = - 0.049至- 0.001)与踝臂指数呈负相关。只有CRP与颈动脉内膜-中膜厚度相关(&bgr;=0.018, 95% CI 0.010 ~ 0.027)。与最低分位数组相比，最高分位数组中重度颈动脉斑块与CRP水平相关的比值比为2.0 (95% CI 1.3 ~ 3.0)。可溶性细胞间粘附分子-1水平与颈动脉斑块密切相关(优势比2.5,95% CI 1.5 - 4.4[最高与最低比值])。可溶性血管细胞粘附分子-1与动脉粥样硬化的任何指标均无显著相关性。本研究表明，CRP与不同部位动脉粥样硬化的严重程度有关。其他标志物与动脉粥样硬化的相关性不太一致。
{"title":"Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study","authors":"I. M. van der Meer, M. D. de Maat, M. Bots, M. Breteler, J. Meijer, A. Kiliaan, A. Hofman, J. Witteman","doi":"10.1161/01.ATV.0000016249.96529.B8","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016249.96529.B8","url":null,"abstract":"Inflammatory mediators and soluble cell adhesion molecules predict cardiovascular events. It is not clear whether they reflect the severity of underlying atherosclerotic disease. Within the Rotterdam Study, we investigated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 with noninvasive measures of atherosclerosis. Levels of CRP were assessed in a random sample of 1317 participants, and levels of IL-6 and soluble cell adhesion molecules were assessed in a subsample of 714 participants. In multivariate analyses, logarithmically transformed CRP (regression coefficient [&bgr;]=−0.023, 95% CI −0.033 to −0.012) and IL-6 (&bgr;=−0.025, 95% CI −0.049 to −0.001) were inversely associated with the ankle-arm index. Only CRP was associated with carotid intima-media thickness (&bgr;=0.018, 95% CI 0.010 to 0.027). Compared with the lowest tertile, the odds ratio for moderate to severe carotid plaques associated with levels of CRP in the highest tertile was 2.0 (95% CI 1.3 to 3.0). Soluble intercellular adhesion molecule-1 levels were strongly associated with carotid plaques (odds ratio 2.5, 95% CI 1.5 to 4.4 [highest versus lowest tertile]). Soluble vascular cell adhesion molecule-1 was not significantly associated with any of the measures of atherosclerosis. This study indicates that CRP is associated with the severity of atherosclerosis measured at various sites. Associations of the other markers with atherosclerosis were less consistent.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83401031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000014587.66321.B4
H. Williams, Jason L. Johnson, K. Carson, C. Jackson
The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109±0.016 mm2; ruptured, 0.192±0.009 mm2;P =0.0005), luminal occlusion (intact, 35.3±3.3%; ruptured, 57.7±1.9%;P <0.0001), the number of buried caps within the lesion (intact, 1.06±0.12; ruptured, 2.66±0.16;P <0.0001), fibrous cap thickness (intact, 4.7±0.6 &mgr;m; ruptured, 2.0±0.3 &mgr;m;P =0.0004), and lipid fractional volume (intact, 35.9±3.0%; ruptured, 50.7±2.2%;P =0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.
{"title":"Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice","authors":"H. Williams, Jason L. Johnson, K. Carson, C. Jackson","doi":"10.1161/01.ATV.0000014587.66321.B4","DOIUrl":"https://doi.org/10.1161/01.ATV.0000014587.66321.B4","url":null,"abstract":"The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. Ruptured and intact plaques differed in terms of plaque cross-sectional area (intact, 0.109±0.016 mm2; ruptured, 0.192±0.009 mm2;P =0.0005), luminal occlusion (intact, 35.3±3.3%; ruptured, 57.7±1.9%;P <0.0001), the number of buried caps within the lesion (intact, 1.06±0.12; ruptured, 2.66±0.16;P <0.0001), fibrous cap thickness (intact, 4.7±0.6 &mgr;m; ruptured, 2.0±0.3 &mgr;m;P =0.0004), and lipid fractional volume (intact, 35.9±3.0%; ruptured, 50.7±2.2%;P =0.0019). This study confirms that plaque rupture is a frequent occurrence in the brachiocephalic arteries of apolipoprotein E knockout mice on a high-fat diet. The data also show that ruptured plaques in these mice show many of the characteristics of vulnerable plaques in humans. This supports the use of this model in studies of the mechanisms and therapy of plaque rupture.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76993370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000015445.22243.F4
I. Juhan-vague, P. Morange, Hélène Aubert, M. Henry, M. Aillaud, M. Alessi, A. Samnegård, E. Hawe, J. Yudkin, M. Margaglione, G. Minno, A. Hamsten, S. Humphries
The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and C+1542G in the 3′ untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, P <0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (P <0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (P =0.03) and San Giovanni Rotondo (P =0.03); the odds ratio for the entire cohort was 0.78 (P <0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the “TAFI-decreasing” alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe.
{"title":"Plasma Thrombin-Activatable Fibrinolysis Inhibitor Antigen Concentration and Genotype in Relation to Myocardial Infarction in the North and South of Europe","authors":"I. Juhan-vague, P. Morange, Hélène Aubert, M. Henry, M. Aillaud, M. Alessi, A. Samnegård, E. Hawe, J. Yudkin, M. Margaglione, G. Minno, A. Hamsten, S. Humphries","doi":"10.1161/01.ATV.0000015445.22243.F4","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015445.22243.F4","url":null,"abstract":"The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and C+1542G in the 3′ untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, P <0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (P <0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (P =0.03) and San Giovanni Rotondo (P =0.03); the odds ratio for the entire cohort was 0.78 (P <0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the “TAFI-decreasing” alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80701565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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