Pub Date : 2002-07-01DOI: 10.1161/01.ATV.0000023187.25914.5B
Haoyi Zheng, C. Dimayuga, Alhakam Hudaihed, S. Katz
Objective—Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. Methods and Results—Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of l-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m2) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1±0.4 &mgr;mol/L at baseline to 14.2±1.3 &mgr;mol/L at 4 hours, P <0.001) and decreased FMD (from 3.8±0.7% at baseline to 1.2±0.5% at 4 hours, P =0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9±1.1 &mgr;mol/L at 4 hours, P =0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5±0.5% at baseline to 5.9±1.1% at 4 hours, P <0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. Conclusions—Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects.
{"title":"Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects","authors":"Haoyi Zheng, C. Dimayuga, Alhakam Hudaihed, S. Katz","doi":"10.1161/01.ATV.0000023187.25914.5B","DOIUrl":"https://doi.org/10.1161/01.ATV.0000023187.25914.5B","url":null,"abstract":"Objective—Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. Methods and Results—Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of l-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m2) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1±0.4 &mgr;mol/L at baseline to 14.2±1.3 &mgr;mol/L at 4 hours, P <0.001) and decreased FMD (from 3.8±0.7% at baseline to 1.2±0.5% at 4 hours, P =0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9±1.1 &mgr;mol/L at 4 hours, P =0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5±0.5% at baseline to 5.9±1.1% at 4 hours, P <0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. Conclusions—Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"56 1","pages":"e1-e4"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85980661","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 : 2002-07-01DOI: 10.1161/01.ATV.0000022847.38083.B6
S. Wassmann, Stefan Hilgers, U. Laufs, M. Böhm, G. Nickenig
ObjectiveObjective—Hypercholesterolemia-induced angiotensin II type 1 (AT1) receptor overexpression is thought to be a key event in the development of endothelial dysfunction. Methods and Results—The effect of a 6-week treatment with the AT1 receptor antagonist candesartan (16 mg/d) on endothelial function and serum inflammation markers was compared with the effect of treatment with placebo or the calcium channel antagonist felodipine (5 mg/d) in 47 hypercholesterolemic patients (low density lipoprotein cholesterol >160 mg/dL). Endothelial function was assessed by measurement of forearm blood flow (FBF) by venous occlusion plethysmography. FBF during reactive hyperemia was significantly improved by candesartan, whereas felodipine and placebo exerted no effect. Nitroglycerin-induced vasorelaxation and basal FBF were not altered significantly. Blood pressure and cholesterol levels were not affected significantly by any drug. Serum concentrations of 8-isoprostane, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were significantly reduced by candesartan treatment but not by placebo or felodipine (ELISA assays). Levels of high-sensitivity C-reactive protein and tumor necrosis factor-&agr; were not altered significantly by any treatment. Conclusions—These data suggest that AT1 receptor antagonism improves endothelial function during hypercholesterolemia and that this applies not only to endothelium-dependent vasodilatation but also to oxidative stress and events involved in monocyte attraction and adhesion. AT1 receptor blockade may potentially represent a novel approach for the prevention of vascular dysfunction associated with hypercholesterolemia that is independent of lipid-lowering and blood pressure–lowering interventions.
{"title":"Angiotensin II Type 1 Receptor Antagonism Improves Hypercholesterolemia-Associated Endothelial Dysfunction","authors":"S. Wassmann, Stefan Hilgers, U. Laufs, M. Böhm, G. Nickenig","doi":"10.1161/01.ATV.0000022847.38083.B6","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022847.38083.B6","url":null,"abstract":"ObjectiveObjective—Hypercholesterolemia-induced angiotensin II type 1 (AT1) receptor overexpression is thought to be a key event in the development of endothelial dysfunction. Methods and Results—The effect of a 6-week treatment with the AT1 receptor antagonist candesartan (16 mg/d) on endothelial function and serum inflammation markers was compared with the effect of treatment with placebo or the calcium channel antagonist felodipine (5 mg/d) in 47 hypercholesterolemic patients (low density lipoprotein cholesterol >160 mg/dL). Endothelial function was assessed by measurement of forearm blood flow (FBF) by venous occlusion plethysmography. FBF during reactive hyperemia was significantly improved by candesartan, whereas felodipine and placebo exerted no effect. Nitroglycerin-induced vasorelaxation and basal FBF were not altered significantly. Blood pressure and cholesterol levels were not affected significantly by any drug. Serum concentrations of 8-isoprostane, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were significantly reduced by candesartan treatment but not by placebo or felodipine (ELISA assays). Levels of high-sensitivity C-reactive protein and tumor necrosis factor-&agr; were not altered significantly by any treatment. Conclusions—These data suggest that AT1 receptor antagonism improves endothelial function during hypercholesterolemia and that this applies not only to endothelium-dependent vasodilatation but also to oxidative stress and events involved in monocyte attraction and adhesion. AT1 receptor blockade may potentially represent a novel approach for the prevention of vascular dysfunction associated with hypercholesterolemia that is independent of lipid-lowering and blood pressure–lowering interventions.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"32 1","pages":"1208-1212"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85535181","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 : 2002-07-01DOI: 10.1161/01.ATV.0000023228.90866.29
U. Tietge, C. Maugeais, S. Lund-Katz, D. Grass, F. Debeer, D. Rader
Objective—Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-I are decreased in inflammatory states. Secretory phospholipase A2 (sPLA2), an acute-phase protein, may play a key role in the pathophysiology of this phenomenon. Methods and Results—To investigate the effects of sPLA2 on human-like HDL particles in vivo, we generated transgenic mice overexpressing human apoA-I and human sPLA2 (apoA-I/sPLA2 mice). Compared with apoA-I mice, apoA-I/sPLA2 mice had significantly lower plasma levels of phospholipids, HDL cholesterol, and apoA-I (each P <0.01). HDL from apoA-I/sPLA2 mice was significantly depleted in phospholipids and cholesteryl esters (each P <0.001) but was enriched in protein and triglycerides (each P <0.001). As assessed by gel filtration and nondenaturing gel electrophoresis, sPLA2 overexpression in apoA-I mice resulted in a dramatic shift of the HDL particle size toward smaller particles. Furthermore, virtually all plasma sPLA2 in apoA-I/sPLA2 mice was found in association with the HDL fraction. The acute-phase response was induced in apoA-I/sPLA2 double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection. Plasma sPLA2 was significantly increased after LPS injection in apoA-I/sPLA2 mice. Twelve hours after LPS administration, plasma total cholesterol, HDL cholesterol, apoA-I, and phospholipids were unchanged in apoA-I transgenic control mice but had decreased significantly in the apoA-I/sPLA2 mice (−57%, −62%, and −54%, −61%, respectively; each P <0.001). Both groups of mice had increased plasma levels of serum amyloid A (SAA) in response to LPS. To test the hypothesis that SAA may be an in vivo activator of sPLA2, we specifically overexpressed SAA in apoA-I/sPLA2 mice by means of liver-directed gene transfer. Despite high plasma levels of SAA, plasma lipid and lipoprotein profiles were not different than those in control mice. Conclusions—These results in a mouse model of human-like HDL indicate that sPLA2 expression significantly influences HDL particle size and composition and demonstrate that an induction of sPLA2 is required for the decrease in plasma HDL cholesterol in response to inflammatory stimuli in mice and that this effect is independent of SAA.
{"title":"Human Secretory Phospholipase A2 Mediates Decreased Plasma Levels of HDL Cholesterol and ApoA-I in Response to Inflammation in Human ApoA-I Transgenic Mice","authors":"U. Tietge, C. Maugeais, S. Lund-Katz, D. Grass, F. Debeer, D. Rader","doi":"10.1161/01.ATV.0000023228.90866.29","DOIUrl":"https://doi.org/10.1161/01.ATV.0000023228.90866.29","url":null,"abstract":"Objective—Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-I are decreased in inflammatory states. Secretory phospholipase A2 (sPLA2), an acute-phase protein, may play a key role in the pathophysiology of this phenomenon. Methods and Results—To investigate the effects of sPLA2 on human-like HDL particles in vivo, we generated transgenic mice overexpressing human apoA-I and human sPLA2 (apoA-I/sPLA2 mice). Compared with apoA-I mice, apoA-I/sPLA2 mice had significantly lower plasma levels of phospholipids, HDL cholesterol, and apoA-I (each P <0.01). HDL from apoA-I/sPLA2 mice was significantly depleted in phospholipids and cholesteryl esters (each P <0.001) but was enriched in protein and triglycerides (each P <0.001). As assessed by gel filtration and nondenaturing gel electrophoresis, sPLA2 overexpression in apoA-I mice resulted in a dramatic shift of the HDL particle size toward smaller particles. Furthermore, virtually all plasma sPLA2 in apoA-I/sPLA2 mice was found in association with the HDL fraction. The acute-phase response was induced in apoA-I/sPLA2 double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection. Plasma sPLA2 was significantly increased after LPS injection in apoA-I/sPLA2 mice. Twelve hours after LPS administration, plasma total cholesterol, HDL cholesterol, apoA-I, and phospholipids were unchanged in apoA-I transgenic control mice but had decreased significantly in the apoA-I/sPLA2 mice (−57%, −62%, and −54%, −61%, respectively; each P <0.001). Both groups of mice had increased plasma levels of serum amyloid A (SAA) in response to LPS. To test the hypothesis that SAA may be an in vivo activator of sPLA2, we specifically overexpressed SAA in apoA-I/sPLA2 mice by means of liver-directed gene transfer. Despite high plasma levels of SAA, plasma lipid and lipoprotein profiles were not different than those in control mice. Conclusions—These results in a mouse model of human-like HDL indicate that sPLA2 expression significantly influences HDL particle size and composition and demonstrate that an induction of sPLA2 is required for the decrease in plasma HDL cholesterol in response to inflammatory stimuli in mice and that this effect is independent of SAA.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"4 5 1","pages":"1213-1218"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75942963","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 : 2002-07-01DOI: 10.1016/S1567-5688(03)90915-9
H. Hao, P. Ropraz, V. Verin, E. Camenzind, A. Geinoz, M. Pepper, G. Gabbiani, M. Bochaton-Piallat
{"title":"Heterogeneity of Smooth Muscle Cell Populations Cultured From Pig Coronary Artery","authors":"H. Hao, P. Ropraz, V. Verin, E. Camenzind, A. Geinoz, M. Pepper, G. Gabbiani, M. Bochaton-Piallat","doi":"10.1016/S1567-5688(03)90915-9","DOIUrl":"https://doi.org/10.1016/S1567-5688(03)90915-9","url":null,"abstract":"","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"82 1","pages":"1093-1099"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79014662","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 : 2002-07-01DOI: 10.1161/01.ATV.0000022015.97341.3A
L. Kuller, A. Arnold, R. Tracy, J. Otvos, G. Burke, B. Psaty, D. Siscovick, D. Freedman, R. Kronmal
Objectives—Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis. Methods and Results—The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 “healthy” participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between “healthy” participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina. Conclusions—Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.
{"title":"Nuclear Magnetic Resonance Spectroscopy of Lipoproteins and Risk of Coronary Heart Disease in the Cardiovascular Health Study","authors":"L. Kuller, A. Arnold, R. Tracy, J. Otvos, G. Burke, B. Psaty, D. Siscovick, D. Freedman, R. Kronmal","doi":"10.1161/01.ATV.0000022015.97341.3A","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022015.97341.3A","url":null,"abstract":"Objectives—Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis. Methods and Results—The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 “healthy” participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between “healthy” participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina. Conclusions—Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"19 1","pages":"1175-1180"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79106176","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 : 2002-07-01DOI: 10.1161/01.ATV.0000023230.17493.E3
C. Sullivan, J. Hoying
Objective—Fibroblast growth factor-2 (FGF2) has been implicated as a mediator in the structural remodeling of arteries. Chronic changes in blood flow are known to cause reorganization of the vessel wall, resulting in permanent changes in artery size (flow-dependent remodeling). Using FGF2 knockout (Fgf2−/−) mice, we tested the hypothesis that FGF2 is required during flow-dependent remodeling of the carotid arteries. Methods and Results—All branches originating from the left common carotid artery (LCCA), except for the left thyroid artery, were ligated to reduce flow in the LCCA and increase flow in the contralateral right common carotid artery (RCCA). Age- and sex-matched control animals did not undergo ligation of the LCCA branches. Morphometric analysis showed that by day 7, vessel diameter was significantly greater in the high-flow RCCA of FGF2 wild-type (Fgf2+/+) and Fgf2−/− mice versus the respective control RCCA, demonstrating outward remodeling. In contrast, vessel diameter was decreased by day 7 in the low-flow LCCA of both genotypes compared with the control LCCA, showing inward remodeling. No differences were observed between Fgf2+/+ and Fgf2−/− mice in either high-flow or low-flow remodeling. Conclusions—Given these results, we demonstrate that FGF2 is not essential for flow-dependent remodeling of the carotid arteries.
{"title":"Flow-Dependent Remodeling in the Carotid Artery of Fibroblast Growth Factor-2 Knockout Mice","authors":"C. Sullivan, J. Hoying","doi":"10.1161/01.ATV.0000023230.17493.E3","DOIUrl":"https://doi.org/10.1161/01.ATV.0000023230.17493.E3","url":null,"abstract":"Objective—Fibroblast growth factor-2 (FGF2) has been implicated as a mediator in the structural remodeling of arteries. Chronic changes in blood flow are known to cause reorganization of the vessel wall, resulting in permanent changes in artery size (flow-dependent remodeling). Using FGF2 knockout (Fgf2−/−) mice, we tested the hypothesis that FGF2 is required during flow-dependent remodeling of the carotid arteries. Methods and Results—All branches originating from the left common carotid artery (LCCA), except for the left thyroid artery, were ligated to reduce flow in the LCCA and increase flow in the contralateral right common carotid artery (RCCA). Age- and sex-matched control animals did not undergo ligation of the LCCA branches. Morphometric analysis showed that by day 7, vessel diameter was significantly greater in the high-flow RCCA of FGF2 wild-type (Fgf2+/+) and Fgf2−/− mice versus the respective control RCCA, demonstrating outward remodeling. In contrast, vessel diameter was decreased by day 7 in the low-flow LCCA of both genotypes compared with the control LCCA, showing inward remodeling. No differences were observed between Fgf2+/+ and Fgf2−/− mice in either high-flow or low-flow remodeling. Conclusions—Given these results, we demonstrate that FGF2 is not essential for flow-dependent remodeling of the carotid arteries.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"89 1","pages":"1100-1105"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85032360","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 : 2002-07-01DOI: 10.1161/01.ATV.0000023427.92642.CD
John M. Gaspar, S. Thai, C. Voland, Antoinise Dube, T. Libermann, M. Iruela-Arispe, P. Oettgen
Objective—The purpose of this study was to evaluate the role of the Ets factor NERF in the regulation of the Tie1 and Tie2 genes during chicken blood vessel development. Methods and Results—We have isolated the full-length cDNA for the chicken homologue of the human Ets factor NERF2 (cNERF2). Northern blot analysis and in situ hybridization demonstrate that cNERF2 is enriched in the developing blood vessels of the chicken chorioallantoic membrane. Interestingly, cNERF2 functions as a competitive inhibitor of a highly related Ets factor cELF-1, which we have previously shown to be enriched in chicken blood vessel development. Although in vitro–translated cELF-1 and cNERF2 can bind equally well to conserved Ets binding sites in the promoters of the Tie1 and Tie2 genes, cELF-1 preferentially binds to the Ets sites in these promoters during early stages of chicken blood vessel development, suggesting that cNERF may bind during later stages of blood vessel development and vascular remodeling. Conclusions—cNERF2 is enriched during embryonic and extraembryonic blood vessel development in the chicken and facilitates tight control of Tie1 and Tie2 gene regulation.
{"title":"Opposing Functions of the Ets Factors NERF and ELF-1 During Chicken Blood Vessel Development","authors":"John M. Gaspar, S. Thai, C. Voland, Antoinise Dube, T. Libermann, M. Iruela-Arispe, P. Oettgen","doi":"10.1161/01.ATV.0000023427.92642.CD","DOIUrl":"https://doi.org/10.1161/01.ATV.0000023427.92642.CD","url":null,"abstract":"Objective—The purpose of this study was to evaluate the role of the Ets factor NERF in the regulation of the Tie1 and Tie2 genes during chicken blood vessel development. Methods and Results—We have isolated the full-length cDNA for the chicken homologue of the human Ets factor NERF2 (cNERF2). Northern blot analysis and in situ hybridization demonstrate that cNERF2 is enriched in the developing blood vessels of the chicken chorioallantoic membrane. Interestingly, cNERF2 functions as a competitive inhibitor of a highly related Ets factor cELF-1, which we have previously shown to be enriched in chicken blood vessel development. Although in vitro–translated cELF-1 and cNERF2 can bind equally well to conserved Ets binding sites in the promoters of the Tie1 and Tie2 genes, cELF-1 preferentially binds to the Ets sites in these promoters during early stages of chicken blood vessel development, suggesting that cNERF may bind during later stages of blood vessel development and vascular remodeling. Conclusions—cNERF2 is enriched during embryonic and extraembryonic blood vessel development in the chicken and facilitates tight control of Tie1 and Tie2 gene regulation.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"30 1","pages":"1106-1112"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82330474","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 : 2002-07-01DOI: 10.1161/01.ATV.0000022382.61262.3E
S. Bagby, Linda S. LeBard, Zaiming Luo, R. Speth, B. Ogden, C. Corless
Objective—To identify vascular cells capable of responding to angiotensin II (Ang II) generated in conduit arteries, we examined the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) in the thoracic aorta (TA) and abdominal aorta (AA) and branches in 90-day fetal, 3-week postnatal, and 6-month adult microswine. Methods and Results—By autoradiography (125I-[Sar1Ile8]-Ang II with or without AT1R- or AT2R-selective analogues or 125I - CGP 42112), there were striking rostrocaudal differences in (1) AT2R binding at all ages (prominent in AA wall and branches, sparse in TA wall and branches) and (2) a non-AT2R binding site for CGP 42112 (consistently evident in postnatal TA and branches but absent in AA and branches). Furthermore, patterns of AT2R distribution in infradiaphragmatic arteries were developmentally distinct. In fetal AAs, high-density AT2Rs occupied the inner 60% of the medial-endothelial wall. In postnatal AAs, AT2Rs were sparse in the medial-endothelial wall but prominent in a circumferential smooth muscle &agr;-actin–negative cell layer at the medial-adventitial border, occupying ≈20% to 25% of the AA cross-sectional area. AT1R density in the TA and AA medial-endothelial wall increased with age, whereas AT2R density decreased after birth. Conclusions—A novel AT2R-positive cell layer confined to postnatal infradiaphragmatic arteries physically links adventitial and medial layers, appears optimally positioned to transduce AT2R-dependent functions of local Ang II, and suggests that adventitial Ang II may elicit regionally distinct vascular responses.
目的:为了鉴定能够对导管动脉血管紧张素II (Ang II)产生反应的血管细胞，我们检测了90天胎儿、出生后3周和6个月成年微猪胸主动脉(TA)和腹主动脉(AA)及其分支中的Ang II 1型受体(AT1R)和Ang II 2型受体(AT2R)。方法和结果:通过放射自显影(125I-[Sar1Ile8]- ang II伴或不伴AT1R或AT2R选择性类似物或125I- CGP 42112)，发现(1)AT2R结合在所有年龄段(在AA壁和分支中突出，在TA壁和分支中稀疏)和(2)CGP 42112的非AT2R结合位点(在出生后的TA和分支中一致明显，但在AA和分支中不存在)存在显著的直立性差异。此外，AT2R在膈下动脉的分布模式在发育过程中是不同的。在胎儿AAs中，高密度的AT2Rs占据了内内皮壁的60%。在出生后的AAs中，AT2Rs在内侧内皮壁稀疏，但在内侧外边界的平滑肌-肌动蛋白阴性细胞层中突出，占AA横截面面积的约20%至25%。TA和AA内侧内皮壁的AT1R密度随年龄增长而增加，而出生后AT2R密度下降。结论:一种新的at2r阳性细胞层局限于出生后的膈下动脉，将外膜层和内膜层物理连接起来，似乎是传导at2r依赖局部Ang II功能的最佳位置，并表明外膜Ang II可能引发区域不同的血管反应。
{"title":"Angiotensin II Type 1 and 2 Receptors in Conduit Arteries of Normal Developing Microswine","authors":"S. Bagby, Linda S. LeBard, Zaiming Luo, R. Speth, B. Ogden, C. Corless","doi":"10.1161/01.ATV.0000022382.61262.3E","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022382.61262.3E","url":null,"abstract":"Objective—To identify vascular cells capable of responding to angiotensin II (Ang II) generated in conduit arteries, we examined the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) in the thoracic aorta (TA) and abdominal aorta (AA) and branches in 90-day fetal, 3-week postnatal, and 6-month adult microswine. Methods and Results—By autoradiography (125I-[Sar1Ile8]-Ang II with or without AT1R- or AT2R-selective analogues or 125I - CGP 42112), there were striking rostrocaudal differences in (1) AT2R binding at all ages (prominent in AA wall and branches, sparse in TA wall and branches) and (2) a non-AT2R binding site for CGP 42112 (consistently evident in postnatal TA and branches but absent in AA and branches). Furthermore, patterns of AT2R distribution in infradiaphragmatic arteries were developmentally distinct. In fetal AAs, high-density AT2Rs occupied the inner 60% of the medial-endothelial wall. In postnatal AAs, AT2Rs were sparse in the medial-endothelial wall but prominent in a circumferential smooth muscle &agr;-actin–negative cell layer at the medial-adventitial border, occupying ≈20% to 25% of the AA cross-sectional area. AT1R density in the TA and AA medial-endothelial wall increased with age, whereas AT2R density decreased after birth. Conclusions—A novel AT2R-positive cell layer confined to postnatal infradiaphragmatic arteries physically links adventitial and medial layers, appears optimally positioned to transduce AT2R-dependent functions of local Ang II, and suggests that adventitial Ang II may elicit regionally distinct vascular responses.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"11 1","pages":"1113-1121"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88733853","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 : 2002-07-01DOI: 10.1161/01.ATV.0000021144.87870.C8
C. Kang, M. Dominguez, S. Loyau, T. Miyata, V. Durlach, E. Anglés-Cano
Objective—Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes. Methods and Results—Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (Kd 3.6±0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC50 16.8±5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (Kd 2.5 versus 10.5 nmol/L and Kd 3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC50 0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10. Conclusions—Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.
{"title":"Lp(a) Particles Mold Fibrin-Binding Properties of Apo(a) in Size-Dependent Manner: A Study With Different-Length Recombinant Apo(a), Native Lp(a), and Monoclonal Antibody","authors":"C. Kang, M. Dominguez, S. Loyau, T. Miyata, V. Durlach, E. Anglés-Cano","doi":"10.1161/01.ATV.0000021144.87870.C8","DOIUrl":"https://doi.org/10.1161/01.ATV.0000021144.87870.C8","url":null,"abstract":"Objective—Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes. Methods and Results—Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (Kd 3.6±0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC50 16.8±5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (Kd 2.5 versus 10.5 nmol/L and Kd 3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC50 0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10. Conclusions—Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"111 1","pages":"1232-1238"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88248294","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 : 2002-07-01DOI: 10.1161/01.ATV.0000022695.22369.BE
A. Tiran, H. Gruber, W. F. Graier, A. Wagner, E. B. van Leeuwen, B. Tiran
Objective—Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-&kgr;B, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae–induced NF-&kgr;B activation, interleukin expression, and bacterial development in cultured human endothelial cells. Methods and Results—Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-&kgr;B inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-&kgr;B was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of the C pneumoniae–induced activation of NF-&kgr;B by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-&kgr;B gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation. Conclusions—These data provide evidence that NF-&kgr;B–mediated gene activation represents a crucial step in the developmental cycle of C pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition of C pneumoniae–induced NF-&kgr;B activation, which might account for some of the cardioprotective activity of aspirin.
{"title":"Aspirin Inhibits Chlamydia pneumoniae–Induced Nuclear Factor-&kgr;B Activation, Cytokine Expression, and Bacterial Development in Human Endothelial Cells","authors":"A. Tiran, H. Gruber, W. F. Graier, A. Wagner, E. B. van Leeuwen, B. Tiran","doi":"10.1161/01.ATV.0000022695.22369.BE","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022695.22369.BE","url":null,"abstract":"Objective—Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-&kgr;B, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae–induced NF-&kgr;B activation, interleukin expression, and bacterial development in cultured human endothelial cells. Methods and Results—Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-&kgr;B inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-&kgr;B was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of the C pneumoniae–induced activation of NF-&kgr;B by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-&kgr;B gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation. Conclusions—These data provide evidence that NF-&kgr;B–mediated gene activation represents a crucial step in the developmental cycle of C pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition of C pneumoniae–induced NF-&kgr;B activation, which might account for some of the cardioprotective activity of aspirin.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"3 1","pages":"1075-1080"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90733901","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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