Pub Date : 2002-08-01DOI: 10.1161/01.ATV.0000024569.80106.B4
S. Kinlay, J. Grewal, Deborah Manuelin, J. Fang, A. Selwyn, J. Bittl, P. Ganz
Objective—Laminar flow becomes disturbed at high velocities, reducing shear stress and augmenting vascular inflammation and proliferation, processes that are pivotal in restenosis and atherogenesis. We hypothesized that disturbed blood flow after coronary angioplasty is associated with adverse long-term clinical outcome. Methods and Results—The cineangiograms from 97 patients undergoing laser-assisted coronary angioplasty were analyzed. Coronary blood flow velocity, the residual lesion dimensions, and the Reynolds number (an index of disturbed flow) were measured by using a frame-counting technique and quantitative coronary angiography. Cox proportional hazards were used to assess the relative risk of adverse events (target-vessel revascularization, myocardial infarction, or death) over a mean 2.5 years after the index procedure. There were 41 adverse events during 245 patient years of follow-up (17% per year of follow-up). The risk of an adverse event was increased for patients with a high flow velocity (>250 mm/s; relative risk 2.5, 95% CI 1.3 to 4.7) or a high Reynolds number (>200) at the stenosis inlet (relative risk 2.1, 95% CI 1.1 to 4.1) at the end of the procedure. Adjustment for other factors did not alter these results. Conclusions—High Reynolds numbers, indicating disturbed blood flow after coronary angioplasty, increase the risk of adverse clinical events, potentially through shear-stress–related molecular mechanisms that promote restenosis and atherogenesis.
{"title":"Coronary Flow Velocity and Disturbed Flow Predict Adverse Clinical Outcome After Coronary Angioplasty","authors":"S. Kinlay, J. Grewal, Deborah Manuelin, J. Fang, A. Selwyn, J. Bittl, P. Ganz","doi":"10.1161/01.ATV.0000024569.80106.B4","DOIUrl":"https://doi.org/10.1161/01.ATV.0000024569.80106.B4","url":null,"abstract":"Objective—Laminar flow becomes disturbed at high velocities, reducing shear stress and augmenting vascular inflammation and proliferation, processes that are pivotal in restenosis and atherogenesis. We hypothesized that disturbed blood flow after coronary angioplasty is associated with adverse long-term clinical outcome. Methods and Results—The cineangiograms from 97 patients undergoing laser-assisted coronary angioplasty were analyzed. Coronary blood flow velocity, the residual lesion dimensions, and the Reynolds number (an index of disturbed flow) were measured by using a frame-counting technique and quantitative coronary angiography. Cox proportional hazards were used to assess the relative risk of adverse events (target-vessel revascularization, myocardial infarction, or death) over a mean 2.5 years after the index procedure. There were 41 adverse events during 245 patient years of follow-up (17% per year of follow-up). The risk of an adverse event was increased for patients with a high flow velocity (>250 mm/s; relative risk 2.5, 95% CI 1.3 to 4.7) or a high Reynolds number (>200) at the stenosis inlet (relative risk 2.1, 95% CI 1.1 to 4.1) at the end of the procedure. Adjustment for other factors did not alter these results. Conclusions—High Reynolds numbers, indicating disturbed blood flow after coronary angioplasty, increase the risk of adverse clinical events, potentially through shear-stress–related molecular mechanisms that promote restenosis and atherogenesis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91226695","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 : 2002-08-01DOI: 10.1161/01.ATV.0000026614.72957.E7
M. Sata, A. Takahashi, Kimie Tanaka, Miwa Washida, N. Ishizaka, J. Ako, M. Yoshizumi, Y. Ouchi, T. Taniguchi, Y. Hirata, M. Yokoyama, R. Nagai, K. Walsh
Objective—N-(3′4′-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. Methods and Results—We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21WAF1 (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21−/−) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen–positive cells in the injured arteries of p21−/− mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21−/− mice. Conclusions—Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.
{"title":"Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21WAF1-Dependent Pathway","authors":"M. Sata, A. Takahashi, Kimie Tanaka, Miwa Washida, N. Ishizaka, J. Ako, M. Yoshizumi, Y. Ouchi, T. Taniguchi, Y. Hirata, M. Yokoyama, R. Nagai, K. Walsh","doi":"10.1161/01.ATV.0000026614.72957.E7","DOIUrl":"https://doi.org/10.1161/01.ATV.0000026614.72957.E7","url":null,"abstract":"Objective—N-(3′4′-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. Methods and Results—We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21WAF1 (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21−/−) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen–positive cells in the injured arteries of p21−/− mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21−/− mice. Conclusions—Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83404034","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 : 2002-08-01DOI: 10.1161/01.ATV.0000027176.83618.1A
Y. T. van der Schouw, A. Pijpe, C. Lebrun, M. Bots, P. Peeters, W. V. van Staveren, S. Lamberts, D. Grobbee
Objective—Phytoestrogens have been postulated to protect against cardiovascular diseases, but few studies have focused on the effect of Western dietary phytoestrogen intake. Methods and Results—Four hundred three women with natural menopause either between 1987 and 1989 or between 1969 and 1979 were selected from the baseline data of the PROSPECT study (n=17 395). Isoflavone and lignan intake was calculated from a food-frequency questionnaire. Aortic stiffness was noninvasively assessed by pulse-wave velocity measurement of the aorta. Linear regression analysis was used. After adjustment for age, body mass index, smoking, physical activity, mean arterial pressure, follow-up time, energy intake, dietary fiber intake, glucose, and high density lipoprotein cholesterol, increasing dietary isoflavone intake was associated with decreased aortic stiffness: −0.51 m/s (95% CI −1.00 to −0.03, fourth versus first quartile, P for trend=0.07). Increasing dietary intake of lignans was also associated with decreased aortic pulse-wave velocity: −0.42 m/s (95% CI −0.93 to 0.11, fourth versus first quartile, P for trend=0.06). Results were most pronounced in older women: for isoflavones, −0.94 m/s (95% CI −1.65 to −0.22, P for trend=0.02), and for lignans, −0.80 m/s (95% CI −1.85 to −0.05), fourth versus first quartile. Conclusions—The results of our study support the view that phytoestrogens have a protective effect on the risk of atherosclerosis and arterial degeneration through an effect on arterial walls, especially among older women.
目的:植物雌激素被认为可以预防心血管疾病，但很少有研究关注西方饮食中植物雌激素的摄入。方法和结果:从PROSPECT研究的基线资料中选择了1987年至1989年或1969年至1979年自然绝经的300名妇女(n= 17395)。异黄酮和木脂素的摄入量是通过食物频率问卷来计算的。通过主动脉脉搏波速度测量无创评估主动脉硬度。采用线性回归分析。在调整了年龄、体重指数、吸烟、体力活动、平均动脉压、随访时间、能量摄入、膳食纤维摄入、葡萄糖和高密度脂蛋白胆固醇等因素后，增加膳食异黄酮摄入量与主动脉僵硬度降低相关:- 0.51 m/s (95% CI为- 1.00至- 0.03，第四与第一四分位数，趋势P =0.07)。增加饮食中木酚素的摄入量也与主动脉脉搏波速度降低有关:- 0.42 m/s (95% CI - 0.93至0.11，第四与第一四分位数，P为趋势=0.06)。结果在老年妇女中最为明显:异黄酮为- 0.94 m/s (95% CI为- 1.65至- 0.22,P为趋势=0.02)，木脂素为- 0.80 m/s (95% CI为- 1.85至- 0.05)，第四和第一四分位数。结论:我们的研究结果支持这样的观点，即植物雌激素通过对动脉壁的作用，对动脉粥样硬化和动脉变性的风险具有保护作用，特别是在老年妇女中。
{"title":"Higher Usual Dietary Intake of Phytoestrogens Is Associated With Lower Aortic Stiffness in Postmenopausal Women","authors":"Y. T. van der Schouw, A. Pijpe, C. Lebrun, M. Bots, P. Peeters, W. V. van Staveren, S. Lamberts, D. Grobbee","doi":"10.1161/01.ATV.0000027176.83618.1A","DOIUrl":"https://doi.org/10.1161/01.ATV.0000027176.83618.1A","url":null,"abstract":"Objective—Phytoestrogens have been postulated to protect against cardiovascular diseases, but few studies have focused on the effect of Western dietary phytoestrogen intake. Methods and Results—Four hundred three women with natural menopause either between 1987 and 1989 or between 1969 and 1979 were selected from the baseline data of the PROSPECT study (n=17 395). Isoflavone and lignan intake was calculated from a food-frequency questionnaire. Aortic stiffness was noninvasively assessed by pulse-wave velocity measurement of the aorta. Linear regression analysis was used. After adjustment for age, body mass index, smoking, physical activity, mean arterial pressure, follow-up time, energy intake, dietary fiber intake, glucose, and high density lipoprotein cholesterol, increasing dietary isoflavone intake was associated with decreased aortic stiffness: −0.51 m/s (95% CI −1.00 to −0.03, fourth versus first quartile, P for trend=0.07). Increasing dietary intake of lignans was also associated with decreased aortic pulse-wave velocity: −0.42 m/s (95% CI −0.93 to 0.11, fourth versus first quartile, P for trend=0.06). Results were most pronounced in older women: for isoflavones, −0.94 m/s (95% CI −1.65 to −0.22, P for trend=0.02), and for lignans, −0.80 m/s (95% CI −1.85 to −0.05), fourth versus first quartile. Conclusions—The results of our study support the view that phytoestrogens have a protective effect on the risk of atherosclerosis and arterial degeneration through an effect on arterial walls, especially among older women.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79684421","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 : 2002-08-01DOI: 10.1161/01.ATV.0000023899.93940.7C
A. Majors, S. Sengupta, B. Willard, M. Kinter, R. Pyeritz, D. Jacobsen
Objective—More than 70% of circulating homocysteine is disulfide-bonded to protein, but little is known about the specific proteins that bind homocysteine and their function as a consequence of homocysteine binding. Methods and Results—When human plasma was incubated with [35S]l-homocysteine, most of the homocysteine bound to albumin. However, additional homocysteine-binding proteins were detected, and 1 of them comigrated with fibronectin. Treatment with 2-mercaptoethanol removed the bound homocysteine, demonstrating the involvement of disulfide bonding. In contrast, [35S]l-cysteine did not bind to fibronectin. Purified fibronectin bound ≈5 homocysteine molecules per fibronectin dimer. SDS-PAGE of a limited trypsin digestion of homocysteinylated fibronectin showed that several tryptic fragments contained [35S]homocysteine. Sequence analysis demonstrated that the fragments containing bound homocysteine had localized mainly to the C-terminal region, within and adjacent to the fibrin-binding domain. Homocysteinylation of fibronectin significantly inhibited its capacity to bind fibrin by 62% (P <0.005). In contrast, neither the binding of fibronectin to gelatin nor its capacity to serve as an attachment factor for aortic smooth muscle cells was affected. Conclusions—These results suggest that homocysteine may alter normal thrombosis and delay or interfere with wound healing by impairing the interaction of fibronectin with fibrin.
{"title":"Homocysteine Binds to Human Plasma Fibronectin and Inhibits Its Interaction With Fibrin","authors":"A. Majors, S. Sengupta, B. Willard, M. Kinter, R. Pyeritz, D. Jacobsen","doi":"10.1161/01.ATV.0000023899.93940.7C","DOIUrl":"https://doi.org/10.1161/01.ATV.0000023899.93940.7C","url":null,"abstract":"Objective—More than 70% of circulating homocysteine is disulfide-bonded to protein, but little is known about the specific proteins that bind homocysteine and their function as a consequence of homocysteine binding. Methods and Results—When human plasma was incubated with [35S]l-homocysteine, most of the homocysteine bound to albumin. However, additional homocysteine-binding proteins were detected, and 1 of them comigrated with fibronectin. Treatment with 2-mercaptoethanol removed the bound homocysteine, demonstrating the involvement of disulfide bonding. In contrast, [35S]l-cysteine did not bind to fibronectin. Purified fibronectin bound ≈5 homocysteine molecules per fibronectin dimer. SDS-PAGE of a limited trypsin digestion of homocysteinylated fibronectin showed that several tryptic fragments contained [35S]homocysteine. Sequence analysis demonstrated that the fragments containing bound homocysteine had localized mainly to the C-terminal region, within and adjacent to the fibrin-binding domain. Homocysteinylation of fibronectin significantly inhibited its capacity to bind fibrin by 62% (P <0.005). In contrast, neither the binding of fibronectin to gelatin nor its capacity to serve as an attachment factor for aortic smooth muscle cells was affected. Conclusions—These results suggest that homocysteine may alter normal thrombosis and delay or interfere with wound healing by impairing the interaction of fibronectin with fibrin.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75717566","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 : 2002-08-01DOI: 10.1161/01.ATV.0000024685.92243.E7
Y. Imai, T. Shindo, K. Maemura, M. Sata, Yuichiro Saito, Y. Kurihara, M. Akishita, J. Osuga, S. Ishibashi, K. Tobe, H. Morita, Y. Oh-hashi, Toru Suzuki, H. Maekawa, K. Kangawa, N. Minamino, Y. Yazaki, R. Nagai, H. Kurihara
Objective—Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). Methods and Results—Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45±0.14 versus 1.31±0.41, respectively;P <0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N&ohgr;-nitro-l-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0±3.9% versus 15.8±2.8%, respectively;P <0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. Conclusions—Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.
{"title":"Resistance to Neointimal Hyperplasia and Fatty Streak Formation in Mice With Adrenomedullin Overexpression","authors":"Y. Imai, T. Shindo, K. Maemura, M. Sata, Yuichiro Saito, Y. Kurihara, M. Akishita, J. Osuga, S. Ishibashi, K. Tobe, H. Morita, Y. Oh-hashi, Toru Suzuki, H. Maekawa, K. Kangawa, N. Minamino, Y. Yazaki, R. Nagai, H. Kurihara","doi":"10.1161/01.ATV.0000024685.92243.E7","DOIUrl":"https://doi.org/10.1161/01.ATV.0000024685.92243.E7","url":null,"abstract":"Objective—Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). Methods and Results—Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45±0.14 versus 1.31±0.41, respectively;P <0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N&ohgr;-nitro-l-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0±3.9% versus 15.8±2.8%, respectively;P <0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. Conclusions—Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73554684","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.0000021759.08060.63
M. Sampson, I. Davies, J. Brown, K. Ivory, D. Hughes
Objective—We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. Methods and Results—Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P <0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P =0.03) . Conclusions—Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.
目的:我们假设急性高血糖(一个独立的心血管危险因素)增加了2型糖尿病和对照组中致动脉粥样硬化白细胞粘附分子的表达，并且这些粘附分子的表达可能是抗氧化敏感的。方法与结果:23例2型糖尿病患者和13例对照患者分别于14天内进行两次口服糖耐量试验，试验期间分别服用安慰剂或口服α -生育酚800 IU /天。激光流式细胞术分别在0、120和240 min检测粘附分子Mac-1、LFA-1和3、ICAM-1和vla4的单核细胞和中性粒细胞表达。基线粘附分子表达在两组之间没有差异，但在葡萄糖负荷后，两组单核细胞Mac-1表达强度都有快速、高度显著的增加(P <0.0001)。补充α -生育酚只降低了糖尿病组Mac-1的表达(P =0.03)。结论:在2型糖尿病患者和对照组中，任何程度的急性血糖漂移都会引起单核细胞Mac-1表达的显著、快速升高。Mac-1介导白细胞血管浸润，是血栓形成的前体。这些数据提示了血糖升高和血管事件发生率增加之间的联系机制。
{"title":"Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients","authors":"M. Sampson, I. Davies, J. Brown, K. Ivory, D. Hughes","doi":"10.1161/01.ATV.0000021759.08060.63","DOIUrl":"https://doi.org/10.1161/01.ATV.0000021759.08060.63","url":null,"abstract":"Objective—We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. Methods and Results—Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P <0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P =0.03) . Conclusions—Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79342028","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.0000020550.65963.E9
N. Sreejayan, Yi Lin, A. Hassid
Objective—Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction. Methods and Results—Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor S-nitroso-N-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor &bgr; subunit and insulin receptor substrate-1, and extracellular signal–regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility. Conclusions—Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia.
{"title":"NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism","authors":"N. Sreejayan, Yi Lin, A. Hassid","doi":"10.1161/01.ATV.0000020550.65963.E9","DOIUrl":"https://doi.org/10.1161/01.ATV.0000020550.65963.E9","url":null,"abstract":"Objective—Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction. Methods and Results—Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor S-nitroso-N-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor &bgr; subunit and insulin receptor substrate-1, and extracellular signal–regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility. Conclusions—Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89781844","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.0000019735.54479.2F
R. Choudhury, V. Fuster, J. Badimón, E. Fisher, Z. Fayad
Noninvasive high-resolution magnetic resonance has the potential to image atherosclerotic plaque and to determine its composition and microanatomy. This review summarizes the rationale for plaque imaging and describes the characteristics of plaque by use of existing MRI techniques. The use of MRI in human disease and in animal models, particularly in rabbits and mice, is presented. Present and future applications of MRI, including real-time vascular intervention, new contrast agents, and molecular imaging, are also discussed.
{"title":"MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging","authors":"R. Choudhury, V. Fuster, J. Badimón, E. Fisher, Z. Fayad","doi":"10.1161/01.ATV.0000019735.54479.2F","DOIUrl":"https://doi.org/10.1161/01.ATV.0000019735.54479.2F","url":null,"abstract":"Noninvasive high-resolution magnetic resonance has the potential to image atherosclerotic plaque and to determine its composition and microanatomy. This review summarizes the rationale for plaque imaging and describes the characteristics of plaque by use of existing MRI techniques. The use of MRI in human disease and in animal models, particularly in rabbits and mice, is presented. Present and future applications of MRI, including real-time vascular intervention, new contrast agents, and molecular imaging, are also discussed.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74625944","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.0000022694.16328.CC
A. Rezaie-Majd, T. Maca, R. Bucek, P. Valent, Michael R. Müller, P. Husslein, A. Kashanipour, E. Minar, M. Baghestanian
Objective—A number of studies have shown that statins decrease morbidity and mortality in patients with cardiovascular diseases. The anti-inflammatory effects of statins have recently been implicated in the clinical benefit that can be obtained in the treatment of atherosclerosis. Little is known about the mechanisms by which statins counteract inflammation. Methods and Results—In this study, we asked whether simvastatin can influence in vitro and in vivo production of the proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. A total of 107 hypercholesterolemic patients were treated with simvastatin. As measured by ELISA, serum levels of cytokines significantly decreased after 6 weeks of treatment (P <0.05). Furthermore, simvastatin decreased the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 mRNA in peripheral blood mononuclear cells. Similar results were obtained in vitro by using cultured human umbilical vein endothelial cells and peripheral blood mononuclear cells from healthy normolipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner. Furthermore, all statins tested were able to reduce the concentrations of cytokines in cellular and extracellular fractions of human umbilical vein endothelial cells (P <0.05). Conclusions—Our data show that simvastatin is anti-inflammatory through the downregulation of cytokines in the endothelium and leukocytes. These effects may explain some of the clinical benefits of these drugs in the treatment of atherosclerosis.
{"title":"Simvastatin Reduces Expression of Cytokines Interleukin-6, Interleukin-8, and Monocyte Chemoattractant Protein-1 in Circulating Monocytes From Hypercholesterolemic Patients","authors":"A. Rezaie-Majd, T. Maca, R. Bucek, P. Valent, Michael R. Müller, P. Husslein, A. Kashanipour, E. Minar, M. Baghestanian","doi":"10.1161/01.ATV.0000022694.16328.CC","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022694.16328.CC","url":null,"abstract":"Objective—A number of studies have shown that statins decrease morbidity and mortality in patients with cardiovascular diseases. The anti-inflammatory effects of statins have recently been implicated in the clinical benefit that can be obtained in the treatment of atherosclerosis. Little is known about the mechanisms by which statins counteract inflammation. Methods and Results—In this study, we asked whether simvastatin can influence in vitro and in vivo production of the proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. A total of 107 hypercholesterolemic patients were treated with simvastatin. As measured by ELISA, serum levels of cytokines significantly decreased after 6 weeks of treatment (P <0.05). Furthermore, simvastatin decreased the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 mRNA in peripheral blood mononuclear cells. Similar results were obtained in vitro by using cultured human umbilical vein endothelial cells and peripheral blood mononuclear cells from healthy normolipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner. Furthermore, all statins tested were able to reduce the concentrations of cytokines in cellular and extracellular fractions of human umbilical vein endothelial cells (P <0.05). Conclusions—Our data show that simvastatin is anti-inflammatory through the downregulation of cytokines in the endothelium and leukocytes. These effects may explain some of the clinical benefits of these drugs in the treatment of atherosclerosis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78696234","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.0000020677.33243.1C
I. Ruel, D. Gaudet, P. Perron, J. Bergeron, P. Julien, B. Lamarche
Objective—The objective of the present study was to compare the impact of the null P207L and defective D9N mutations in the LPL gene on LDL particle size among heterozygous carriers. Methods and Results—LDL particle size was measured on whole plasma by 2% to 16% non-denaturing polyacrylamide gradient gel electrophoresis in a cohort of 206 heterozygous carriers of either the P207L or the D9N mutation. The P207L carriers (N=88) presented with a more atherogenic lipoprotein-lipid profile compared with the D9N carriers (N=118). Accordingly, LDL particle size was smaller in the P207L carriers than in the D9N subjects (248.8± 1.0 vs 254.5±1.0 Å, P < 0.001), and the difference remained significant after adjustment for plasma triglyceride (TG) levels. The difference in LDL diameter between the P207L and the D9N carriers was 3-fold greater in individuals with plasma TG levels >3.5 mmol/L than in subjects with TG ≤3.5 mmol/L. The factors that statistically contributed to LDL particle size variation in multivariate analyses were plasma TG levels (11.6%) and age (6.4%) in subjects with TG levels ≤3.5 mmol/L and HDL cholesterol levels (15.5%) and the LPL gene mutation (null versus defective, 7.0%) in patients with TG levels >3.5 mmol/L. Conclusions—These results suggest that the null P207L mutation in the LPL gene has a greater impact on LDL particle size than the defective D9N mutation and that this mutation-specific effect is amplified at greater plasma TG concentrations.
目的:本研究的目的是比较LPL基因P207L缺失和D9N缺陷突变对杂合携带者LDL颗粒大小的影响。方法与结果:对206例P207L或D9N突变杂合携带者，采用2% ~ 16%非变性聚丙烯酰胺梯度凝胶电泳法测定全血浆ldl粒径。与D9N携带者(N=118)相比，P207L携带者(N=88)表现出更强的致动脉粥样硬化性脂蛋白-脂质谱。因此，P207L携带者的LDL颗粒尺寸小于D9N受试者(248.8±1.0 vs 254.5±1.0 Å， P < 0.001)，并且在调整血浆甘油三酯(TG)水平后差异仍然显著。血浆TG水平>3.5 mmol/L的P207L和D9N携带者LDL直径的差异是TG≤3.5 mmol/L的3倍。多因素分析中对LDL粒径变化有统计学影响的因素为TG≤3.5 mmol/L和HDL胆固醇≤15.5%的受试者血浆TG水平(11.6%)和年龄(6.4%)，以及TG >3.5 mmol/L的患者LPL基因突变(无效vs缺陷，7.0%)。结论:这些结果表明，LPL基因的无基因P207L突变比缺陷基因D9N突变对LDL颗粒大小的影响更大，并且这种突变特异性效应在血浆TG浓度较高时被放大。
{"title":"Characterization of LDL Particle Size Among Carriers of a Defective or a Null Mutation in the Lipoprotein Lipase Gene: The Québec LIPD Study","authors":"I. Ruel, D. Gaudet, P. Perron, J. Bergeron, P. Julien, B. Lamarche","doi":"10.1161/01.ATV.0000020677.33243.1C","DOIUrl":"https://doi.org/10.1161/01.ATV.0000020677.33243.1C","url":null,"abstract":"Objective—The objective of the present study was to compare the impact of the null P207L and defective D9N mutations in the LPL gene on LDL particle size among heterozygous carriers. Methods and Results—LDL particle size was measured on whole plasma by 2% to 16% non-denaturing polyacrylamide gradient gel electrophoresis in a cohort of 206 heterozygous carriers of either the P207L or the D9N mutation. The P207L carriers (N=88) presented with a more atherogenic lipoprotein-lipid profile compared with the D9N carriers (N=118). Accordingly, LDL particle size was smaller in the P207L carriers than in the D9N subjects (248.8± 1.0 vs 254.5±1.0 Å, P < 0.001), and the difference remained significant after adjustment for plasma triglyceride (TG) levels. The difference in LDL diameter between the P207L and the D9N carriers was 3-fold greater in individuals with plasma TG levels >3.5 mmol/L than in subjects with TG ≤3.5 mmol/L. The factors that statistically contributed to LDL particle size variation in multivariate analyses were plasma TG levels (11.6%) and age (6.4%) in subjects with TG levels ≤3.5 mmol/L and HDL cholesterol levels (15.5%) and the LPL gene mutation (null versus defective, 7.0%) in patients with TG levels >3.5 mmol/L. Conclusions—These results suggest that the null P207L mutation in the LPL gene has a greater impact on LDL particle size than the defective D9N mutation and that this mutation-specific effect is amplified at greater plasma TG concentrations.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79592805","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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