Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017994.77066.75
D. Kuhel, B. Zhu, D. Witte, D. Hui
Five inbred strains of mice differing in susceptibility to diet-induced atherosclerosis were compared for neointimal hyperplasia after endothelial denudation with an epoxy resin–modified catheter probe. Results showed that all animals responded similarly to the arterial injury, with increased medial area and thickness after 14 days. In contrast, a significant strain-specific difference in neointimal formation after injury was observed. The atherosclerosis-susceptible C57L/J mice were also susceptible to injury-induced neointimal hyperplasia, and the C3H mice were resistant to both forms of vascular diseases. The 129/Sv mice, which displayed an intermediate level of diet-induced atherosclerosis, also displayed an intermediate level of injury-induced neointimal hyperplasia. Interestingly, the atherosclerosis-susceptible C57BL/6 mice were resistant to neointimal hyperplasia after endothelial denudation, whereas the atherosclerosis-resistant FVB/N mice were susceptible, displaying massive neointimal hyperplasia after arterial injury. All (C57L/J×C57BL/6)F1 hybrid mice were resistant to injury-induced neointimal hyperplasia. Moreover, N2 mice generated from backcrossing the F1 hybrid mice to the susceptible C57L/J mice displayed a range of arterial response to injury, spanning the most severe to the most resistant phenotype. These results indicate that injury-induced neointimal hyperplasia and diet-induced atherosclerosis are controlled by distinct sets of genes; the former appeared to be determined by recessive genes at ≥2 loci.
{"title":"Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice","authors":"D. Kuhel, B. Zhu, D. Witte, D. Hui","doi":"10.1161/01.ATV.0000017994.77066.75","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017994.77066.75","url":null,"abstract":"Five inbred strains of mice differing in susceptibility to diet-induced atherosclerosis were compared for neointimal hyperplasia after endothelial denudation with an epoxy resin–modified catheter probe. Results showed that all animals responded similarly to the arterial injury, with increased medial area and thickness after 14 days. In contrast, a significant strain-specific difference in neointimal formation after injury was observed. The atherosclerosis-susceptible C57L/J mice were also susceptible to injury-induced neointimal hyperplasia, and the C3H mice were resistant to both forms of vascular diseases. The 129/Sv mice, which displayed an intermediate level of diet-induced atherosclerosis, also displayed an intermediate level of injury-induced neointimal hyperplasia. Interestingly, the atherosclerosis-susceptible C57BL/6 mice were resistant to neointimal hyperplasia after endothelial denudation, whereas the atherosclerosis-resistant FVB/N mice were susceptible, displaying massive neointimal hyperplasia after arterial injury. All (C57L/J×C57BL/6)F1 hybrid mice were resistant to injury-induced neointimal hyperplasia. Moreover, N2 mice generated from backcrossing the F1 hybrid mice to the susceptible C57L/J mice displayed a range of arterial response to injury, spanning the most severe to the most resistant phenotype. These results indicate that injury-induced neointimal hyperplasia and diet-induced atherosclerosis are controlled by distinct sets of genes; the former appeared to be determined by recessive genes at ≥2 loci.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76627556","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 : 2002-06-01DOI: 10.1161/01.ATV.0000017461.79231.3D
K. Arakawa, K. Isoda, Toshimitu Ito, K. Nakajima, T. Shibuya, F. Ohsuzu
Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser–induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r =0.65, P <0.0001), especially at a thickness of <200 &mgr;m. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.
易损斑块通常包含薄纤维帽、脂质池和减少的内部斑块胶原蛋白。动脉荧光分析可以区分动脉粥样硬化病变与正常动脉;然而，脂质核心对动脉粥样硬化动脉荧光的贡献仍然存在争议。本研究旨在鉴定脂质核心荧光团，并将脂质核心与正常动脉和动脉粥样硬化区分开。记录了氦镉激光诱导的尸体动脉和已知化学成分的荧光光谱。与正常组织和动脉粥样硬化组织相比，脂质核荧光光谱出现明显的红移和增宽。脂核和氧化低密度脂蛋白，动脉粥样硬化和胶原蛋白，正常动脉和弹性蛋白的荧光光谱相似。基于胶原蛋白、弹性蛋白和氧化低密度脂蛋白光谱分解的分类可以区分脂质核心(n=29)、正常动脉(n=74)、动脉粥样硬化(n=73)和动脉粥样硬化前期(n=10)，准确率为86%。纤维帽厚度与光谱胶原含量指数相关(r =0.65, P <0.0001)，特别是在纤维帽厚度<200 &mgr;m时。我们认为，基于化学光谱分解的分类算法可以准确地对正常动脉、动脉粥样硬化和脂质核心的荧光光谱进行分类，可能有助于识别体内易损动脉粥样硬化。
{"title":"Fluorescence Analysis of Biochemical Constituents Identifies Atherosclerotic Plaque With a Thin Fibrous Cap","authors":"K. Arakawa, K. Isoda, Toshimitu Ito, K. Nakajima, T. Shibuya, F. Ohsuzu","doi":"10.1161/01.ATV.0000017461.79231.3D","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017461.79231.3D","url":null,"abstract":"Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser–induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r =0.65, P <0.0001), especially at a thickness of <200 &mgr;m. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77819327","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 : 2002-06-01DOI: 10.1161/01.ATV.0000017470.08363.AB
A. Folsom, N. Aleksic, Lu Wang, M. Cushman, Kenneth K. Wu, R. White
Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for ≈2.5% of venous thromboembolic events in the ARIC population.
虽然已知缺乏蛋白C和抗凝血酶(两种天然血浆抗凝剂)是静脉血栓形成的危险因素，但缺乏基于人群的前瞻性发病率数据。两项纵向队列研究——社区动脉粥样硬化风险研究(ARIC)和心血管健康研究(CHS)已经在成人中发现了静脉血栓栓塞事件。发病率与诊断前血浆蛋白C(仅限ARIC研究)和抗凝血酶水平有关。在平均8.1年的随访中，在ARIC研究中有130例非癌症引起的静脉血栓栓塞事件。在1.1%的蛋白C值<2.0 mg/L的受试者中，与蛋白C值较高的受试者相比，年龄调整后的发病率增加了3.36倍(95% CI 1.24 ~ 9.11)。相比之下，在ARIC研究和CHS中，低血浆抗凝血酶与静脉血栓栓塞之间没有关联。总之，在这项基于人群的研究中，低蛋白C(而非抗凝血酶)水平已被确定与静脉血栓栓塞发生率增加有关。归因风险估计表明，在ARIC人群中，低蛋白C水平约占静脉血栓栓塞事件的2.5%。
{"title":"Protein C, Antithrombin, and Venous Thromboembolism Incidence: A Prospective Population-Based Study","authors":"A. Folsom, N. Aleksic, Lu Wang, M. Cushman, Kenneth K. Wu, R. White","doi":"10.1161/01.ATV.0000017470.08363.AB","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017470.08363.AB","url":null,"abstract":"Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for ≈2.5% of venous thromboembolic events in the ARIC population.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84356413","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.0000014742.56572.25
R. Henriksen, V. Hanks
Previous reports have indicated that thrombin-induced thromboxane production by human platelets occurs through two types of interaction between thrombin and the platelet surface. One of these interactions is with protease activated receptor(PAR)-1, the first identified thrombin receptor. These studies were undertaken to determine whether stimulation of PAR-4 also results in thromboxane production. The results show that treatment of washed human platelets with the PAR-4 agonist AYPGKF stimulates a maximum of 40% to 60% of the thromboxane produced by 100 nmol/L thrombin. Maximal thromboxane production requires approximately 1.0 mmol/L AYPGKF, despite the observation that maximal aggregation is produced by 45 &mgr;mol/L AYPGKF. Thromboxane produced by the combined stimulation of PAR-1 and PAR-4 is additive. Pretreatment of platelets with 45 &mgr;mol/L AYPGKF partially desensitizes thromboxane production in response to higher concentrations of AYPGKF and thrombin but not to stimulation by SFLLRN. PAR-4–induced stimulation is also significantly inhibited by 60 &mgr;mol/L genistein. It is concluded that activation through either PAR-1 or PAR-4 results in thromboxane production, but that stimulation of neither receptor alone produces thromboxane equivalent to that produced by 100 nmol/L thrombin. Thus, these findings demonstrate the presence of two pathways for thrombin-induced thromboxane production by platelets as proposed previously.
{"title":"PAR-4 Agonist AYPGKF Stimulates Thromboxane Production by Human Platelets","authors":"R. Henriksen, V. Hanks","doi":"10.1161/01.ATV.0000014742.56572.25","DOIUrl":"https://doi.org/10.1161/01.ATV.0000014742.56572.25","url":null,"abstract":"Previous reports have indicated that thrombin-induced thromboxane production by human platelets occurs through two types of interaction between thrombin and the platelet surface. One of these interactions is with protease activated receptor(PAR)-1, the first identified thrombin receptor. These studies were undertaken to determine whether stimulation of PAR-4 also results in thromboxane production. The results show that treatment of washed human platelets with the PAR-4 agonist AYPGKF stimulates a maximum of 40% to 60% of the thromboxane produced by 100 nmol/L thrombin. Maximal thromboxane production requires approximately 1.0 mmol/L AYPGKF, despite the observation that maximal aggregation is produced by 45 &mgr;mol/L AYPGKF. Thromboxane produced by the combined stimulation of PAR-1 and PAR-4 is additive. Pretreatment of platelets with 45 &mgr;mol/L AYPGKF partially desensitizes thromboxane production in response to higher concentrations of AYPGKF and thrombin but not to stimulation by SFLLRN. PAR-4–induced stimulation is also significantly inhibited by 60 &mgr;mol/L genistein. It is concluded that activation through either PAR-1 or PAR-4 results in thromboxane production, but that stimulation of neither receptor alone produces thromboxane equivalent to that produced by 100 nmol/L thrombin. Thus, these findings demonstrate the presence of two pathways for thrombin-induced thromboxane production by platelets as proposed previously.","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":"78715872","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.0000013313.70875.A7
L. Jartti, T. Rönnemaa, J. Kaprio, M. Järvisalo, J. Toikka, J. Marniemi, N. Hammar, L. Alfredsson, M. Saraste, J. Hartiala, M. Koskenvuo, O. Raitakari
Finnish men have higher coronary heart disease (CHD) mortality than Swedish men do. To assess the impact of migration to a country with lower CHD mortality on subclinical atherosclerosis, we measured early functional and structural atherosclerotic vascular changes in twins discordant for migration from Finland to Sweden. Conventional CHD risk factors, flow-mediated dilatation (FMD) of the brachial artery, carotid intima-media thickness, and carotid artery compliance were measured in 74 male twin pairs (20 monozygous, 54 dizygous), aged 42 to 69 years, in which co-one twin had migrated more than 20 years ago permanently to Sweden. There were no significant differences in CHD risk factors except for diastolic blood pressure and body fat percentage, which were higher in Sweden. In all subjects, mean FMD was non-significantly higher in Sweden (5.7±4.3% vs 4.9±4.2%, P =0.22), but in monozygous twins the difference in FMD was highly significant (7.2±4.4 vs 3.7±2.9%, P =0.003). There was no significant difference in intima-media thickness or carotid artery compliance between Sweden and Finland. We conclude that in Finnish monozygous twins the endothelial function is better among the twins that have migrated to a country with lower CHD prevalence.
芬兰男性冠心病(CHD)死亡率高于瑞典男性。为了评估移民到冠心病死亡率较低的国家对亚临床动脉粥样硬化的影响，我们测量了从芬兰移民到瑞典的双胞胎早期功能和结构动脉粥样硬化血管的变化。我们测量了74对42 - 69岁的男性双胞胎(20对同卵双胞胎，54对异卵双胞胎)的常规冠心病危险因素、肱动脉血流介导扩张(FMD)、颈动脉内膜-中膜厚度和颈动脉顺应性，其中双胞胎中的一个在20多年前永久移民到瑞典。除了舒张压和体脂率在瑞典较高外，冠心病的危险因素没有显著差异。在所有受试者中，瑞典的平均FMD无显著性升高(5.7±4.3% vs 4.9±4.2%，P =0.22)，但在同卵双胞胎中，FMD的差异非常显著(7.2±4.4 vs 3.7±2.9%，P =0.003)。瑞典和芬兰在颈动脉内膜-中膜厚度和颈动脉顺应性方面没有显著差异。我们得出结论，在芬兰同卵双胞胎中，移居到冠心病患病率较低的国家的双胞胎内皮功能更好。
{"title":"Population-Based Twin Study of the Effects of Migration From Finland to Sweden on Endothelial Function and Intima-Media Thickness","authors":"L. Jartti, T. Rönnemaa, J. Kaprio, M. Järvisalo, J. Toikka, J. Marniemi, N. Hammar, L. Alfredsson, M. Saraste, J. Hartiala, M. Koskenvuo, O. Raitakari","doi":"10.1161/01.ATV.0000013313.70875.A7","DOIUrl":"https://doi.org/10.1161/01.ATV.0000013313.70875.A7","url":null,"abstract":"Finnish men have higher coronary heart disease (CHD) mortality than Swedish men do. To assess the impact of migration to a country with lower CHD mortality on subclinical atherosclerosis, we measured early functional and structural atherosclerotic vascular changes in twins discordant for migration from Finland to Sweden. Conventional CHD risk factors, flow-mediated dilatation (FMD) of the brachial artery, carotid intima-media thickness, and carotid artery compliance were measured in 74 male twin pairs (20 monozygous, 54 dizygous), aged 42 to 69 years, in which co-one twin had migrated more than 20 years ago permanently to Sweden. There were no significant differences in CHD risk factors except for diastolic blood pressure and body fat percentage, which were higher in Sweden. In all subjects, mean FMD was non-significantly higher in Sweden (5.7±4.3% vs 4.9±4.2%, P =0.22), but in monozygous twins the difference in FMD was highly significant (7.2±4.4 vs 3.7±2.9%, P =0.003). There was no significant difference in intima-media thickness or carotid artery compliance between Sweden and Finland. We conclude that in Finnish monozygous twins the endothelial function is better among the twins that have migrated to a country with lower CHD prevalence.","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":"79498222","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.0000014588.71807.0A
J. Symons, A. Mullick, J. Ensunsa, Amy Ma, J. Rutledge, D. Symons
High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4 &mgr;mol/L, respectively. Maximal acetylcholine-evoked relaxation (≈40% vs ≈60%) and tension development from baseline in response to nitric oxide synthase inhibition (≈20% vs ≈40%) were lower (both P <0.05) in coronary resistance vessels (≈120 &mgr;m, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was ≈44% and ≈24% greater (P <0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less (≈32% vs 42%, P <0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (P <0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.
{"title":"Hyperhomocysteinemia Evoked by Folate Depletion: Effects on Coronary and Carotid Arterial Function","authors":"J. Symons, A. Mullick, J. Ensunsa, Amy Ma, J. Rutledge, D. Symons","doi":"10.1161/01.ATV.0000014588.71807.0A","DOIUrl":"https://doi.org/10.1161/01.ATV.0000014588.71807.0A","url":null,"abstract":"High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4 &mgr;mol/L, respectively. Maximal acetylcholine-evoked relaxation (≈40% vs ≈60%) and tension development from baseline in response to nitric oxide synthase inhibition (≈20% vs ≈40%) were lower (both P <0.05) in coronary resistance vessels (≈120 &mgr;m, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was ≈44% and ≈24% greater (P <0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less (≈32% vs 42%, P <0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (P <0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.","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":"86854942","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.0000015884.61894.DC
Mushtaq Ahmad, Yan Zhang, Yong Zhang, Christopher Papharalambus, R. Alexander
We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-l-cysteine (AFC) or N-acetyl-S-geranylgeranyl-l-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-&agr; (TNF-&agr;) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-&agr; stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-&agr;. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-&agr; stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.
我们之前已经表明，细胞因子刺激血管细胞粘附分子-1 (VCAM-1)的表达，而不是细胞间粘附分子-1 (ICAM-1)的表达，在内皮细胞中是氧化还原敏感的。在这里，我们研究了异戊酰半胱氨酸羧甲基转移酶(ICMTase)的作用，该酶能甲基化异戊酰化CAAX(其中C表示半胱氨酸;A，脂肪族氨基酸;和X，几乎任何其他氨基酸)蛋白质，包括Rac1，一种产生超氧化物的NAD(P)H氧化酶的成分，在VCAM-1的表达中。特异性ICMTase抑制剂n -乙酰基- s -法尼基-l-半胱氨酸(AFC)或n -乙酰基- s -香叶基-l-半胱氨酸(AGGC)预处理内皮细胞可抑制肿瘤坏死因子-&agr;(TNF-&agr;)刺激VCAM-1 mRNA表达，但对ICAM-1无影响。内皮细胞表达了组成性活性的ICMTase，这表明细胞中存在甲基化的Rac1和AFC。TNF -&agr;刺激细胞显著增加内皮细胞中AFC和Rac1的甲基化。ICMTase是氧化还原敏感信号通路的一个组成部分，TNF-&agr;对活性氧产生的AFC抑制也表明了这一点。有趣的是，Rac1的显性阴性亚型没有选择性，而是抑制TNF-&agr;刺激VCAM-1和ICAM-1 mRNA表达。因此，ICMTase是氧化还原敏感的vcam -1选择性信号通路的关键组成部分，它似乎通过Rac1的甲基化激活了一个离散的炎症信号通路，至少部分是这样。
{"title":"Role of Isoprenylcysteine Carboxyl Methyltransferase in Tumor Necrosis Factor-&agr; Stimulation of Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells","authors":"Mushtaq Ahmad, Yan Zhang, Yong Zhang, Christopher Papharalambus, R. Alexander","doi":"10.1161/01.ATV.0000015884.61894.DC","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015884.61894.DC","url":null,"abstract":"We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-l-cysteine (AFC) or N-acetyl-S-geranylgeranyl-l-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-&agr; (TNF-&agr;) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-&agr; stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-&agr;. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-&agr; stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.","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":"83420334","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.0000015330.64968.C4
R. V. van Etten, E. D. de Koning, M. Honing, E. Stroes, C. Gaillard, T. Rabelink
Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts cardiovascular outcome. Type 2 diabetes is characterized by endothelial dysfunction, which may be caused by dyslipidemia. Statin therapy restores endothelial function in hyperlipidemic patients. Therefore, we hypothesize a beneficial effect of atorvastatin on NO-dependent vasodilation in patients with type 2 diabetes and mild dyslipidemia (low density lipoproteins >4.0 mmol/L and/or triglycerides >1.8 mmol/L). We evaluated the effect of intensive lipid lowering (4 weeks of 80 mg atorvastatin once daily) on vasoreactivity in 23 patients with type 2 diabetes by using venous occlusion plethysmography. Twenty-one control subjects were matched for age, sex, body mass index, blood pressure, and smoking habits. The ratio of blood flows in the infused (measurement [M]) and noninfused (control [C]) arm was calculated for each recording (M/C ratio), and M/C% indicates the percentage change from the baseline M/C ratio. Serotonin-induced NO-dependent vasodilation was significantly blunted (52±30 versus 102±66 M/C%, P <0.005), and nitroprusside-induced endothelium-independent vasodilation was modestly reduced (275±146 versus 391±203 M/C%, P <0.05) in patients with type 2 diabetes compared with control subjects. Despite significant reduction of total cholesterol, low density lipoproteins, and triglycerides (5.8±1.0 to 3.2±0.6 [P <0.0001], 4.1±1.1 to 1.8±0.7 [P <0.0001], and 2.2±1.3 to 1.4±0.5 [P <0.05] mmol/L, respectively), no effect on NO-dependent (59±44 M/C%) and endothelium-independent (292±202 M/C%) vasodilation was demonstrated. These data suggest that intensive lipid lowering by atorvastatin has no effect on NO availability in forearm resistance arteries in type 2 diabetic patients. Other factors, such as hyperglycemia, may be a more important contributing factor regarding impaired vasoreactivity in this patient group.
心血管疾病是2型糖尿病患者发病和死亡的最重要原因。内皮功能障碍预测心血管预后。2型糖尿病的特点是内皮功能障碍，可能是由血脂异常引起的。他汀类药物治疗可恢复高脂血症患者的内皮功能。因此，我们假设阿托伐他汀对2型糖尿病和轻度血脂异常(低密度脂蛋白>4.0 mmol/L和/或甘油三酯>1.8 mmol/L)患者一氧化氮依赖性血管舒张有有益作用。我们通过静脉闭塞容积描记术评估了23例2型糖尿病患者强化降脂(4周80 mg阿托伐他汀每日1次)对血管反应性的影响。21名对照受试者根据年龄、性别、体重指数、血压和吸烟习惯进行匹配。每次记录时计算输注组(测量组[M])和未输注组(对照组[C])的血流量比(M/C比)，M/C%表示与基线M/C比相比的变化百分比。与对照组相比，2型糖尿病患者血清素诱导的no依赖性血管舒张明显减弱(52±30对102±66 M/C%， P <0.005)，硝普塞诱导的内皮依赖性血管舒张适度降低(275±146对391±203 M/C%， P <0.05)。尽管总胆固醇、低密度脂蛋白和甘油三酯显著降低(分别为5.8±1.0至3.2±0.6 [P <0.0001]、4.1±1.1至1.8±0.7 [P <0.0001]和2.2±1.3至1.4±0.5 [P <0.05] mmol/L)，但对no依赖性(59±44 M/C%)和内皮依赖性(292±202 M/C%)血管舒张无影响。这些数据表明，阿托伐他汀强化降脂对2型糖尿病患者前臂阻力动脉no可用性没有影响。其他因素，如高血糖，可能是导致该患者组血管反应性受损的更重要因素。
{"title":"Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes","authors":"R. V. van Etten, E. D. de Koning, M. Honing, E. Stroes, C. Gaillard, T. Rabelink","doi":"10.1161/01.ATV.0000015330.64968.C4","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015330.64968.C4","url":null,"abstract":"Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts cardiovascular outcome. Type 2 diabetes is characterized by endothelial dysfunction, which may be caused by dyslipidemia. Statin therapy restores endothelial function in hyperlipidemic patients. Therefore, we hypothesize a beneficial effect of atorvastatin on NO-dependent vasodilation in patients with type 2 diabetes and mild dyslipidemia (low density lipoproteins >4.0 mmol/L and/or triglycerides >1.8 mmol/L). We evaluated the effect of intensive lipid lowering (4 weeks of 80 mg atorvastatin once daily) on vasoreactivity in 23 patients with type 2 diabetes by using venous occlusion plethysmography. Twenty-one control subjects were matched for age, sex, body mass index, blood pressure, and smoking habits. The ratio of blood flows in the infused (measurement [M]) and noninfused (control [C]) arm was calculated for each recording (M/C ratio), and M/C% indicates the percentage change from the baseline M/C ratio. Serotonin-induced NO-dependent vasodilation was significantly blunted (52±30 versus 102±66 M/C%, P <0.005), and nitroprusside-induced endothelium-independent vasodilation was modestly reduced (275±146 versus 391±203 M/C%, P <0.05) in patients with type 2 diabetes compared with control subjects. Despite significant reduction of total cholesterol, low density lipoproteins, and triglycerides (5.8±1.0 to 3.2±0.6 [P <0.0001], 4.1±1.1 to 1.8±0.7 [P <0.0001], and 2.2±1.3 to 1.4±0.5 [P <0.05] mmol/L, respectively), no effect on NO-dependent (59±44 M/C%) and endothelium-independent (292±202 M/C%) vasodilation was demonstrated. These data suggest that intensive lipid lowering by atorvastatin has no effect on NO availability in forearm resistance arteries in type 2 diabetic patients. Other factors, such as hyperglycemia, may be a more important contributing factor regarding impaired vasoreactivity in this patient group.","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":"74637292","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.0000016153.47693.B2
S. Prescott, T. McIntyre, G. Zimmerman, D. Stafforini
The inflammatory response is characterized by a multistep molecular interaction between “signaling” cells, such as endothelial cells, and “responding” cells, such as neutrophils and monocytes. In the first step, selectins produced by signaling cells mediate the tethering of responding cells at sites of inflammation. Subsequently, an additional mediator expressed by signaling cells activates the tethered responding cells. Under pathological conditions, the same mechanism is invoked in inappropriate ways: (1) by prolonged presentation of selectins on the cell surface and (2) by the unregulated production of oxidized phospholipids that mimic the normal secondary signaling molecule, platelet-activating factor (PAF). The enzyme PAF acetylhydrolase (PAF-AH) inactivates PAF and oxidized phospholipids and constitutes an “off” switch that suppresses inflammation. Inhibition of normal PAF-AH function or inactivating mutations of the PAF-AH gene can lead to increased susceptibility to inflammatory disease. These studies have relevance to atherosclerosis and thrombosis, because inflammation is a central feature of both.
{"title":"Sol Sherry Lecture in Thrombosis: Molecular Events in Acute Inflammation","authors":"S. Prescott, T. McIntyre, G. Zimmerman, D. Stafforini","doi":"10.1161/01.ATV.0000016153.47693.B2","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016153.47693.B2","url":null,"abstract":"The inflammatory response is characterized by a multistep molecular interaction between “signaling” cells, such as endothelial cells, and “responding” cells, such as neutrophils and monocytes. In the first step, selectins produced by signaling cells mediate the tethering of responding cells at sites of inflammation. Subsequently, an additional mediator expressed by signaling cells activates the tethered responding cells. Under pathological conditions, the same mechanism is invoked in inappropriate ways: (1) by prolonged presentation of selectins on the cell surface and (2) by the unregulated production of oxidized phospholipids that mimic the normal secondary signaling molecule, platelet-activating factor (PAF). The enzyme PAF acetylhydrolase (PAF-AH) inactivates PAF and oxidized phospholipids and constitutes an “off” switch that suppresses inflammation. Inhibition of normal PAF-AH function or inactivating mutations of the PAF-AH gene can lead to increased susceptibility to inflammatory disease. These studies have relevance to atherosclerosis and thrombosis, because inflammation is a central feature of both.","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":"82087831","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.0000015598.86369.04
O. Barbier, I. Torra, Y. Duguay, C. Blanquart, J. Fruchart, C. Glineur, B. Staels
Peroxisome proliferator–activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPAR&agr; mediates the hypolipidemic action of fibrates, PPAR&ggr; is the receptor for the antidiabetic glitazones. PPAR&agr; is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the &bgr;-oxidative degradation of fatty acids. PPAR&ggr; is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPAR&bgr;/&dgr; is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPAR&agr; controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPAR&agr; and PPAR&ggr; regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.
{"title":"Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis","authors":"O. Barbier, I. Torra, Y. Duguay, C. Blanquart, J. Fruchart, C. Glineur, B. Staels","doi":"10.1161/01.ATV.0000015598.86369.04","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015598.86369.04","url":null,"abstract":"Peroxisome proliferator–activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. Although PPAR&agr; mediates the hypolipidemic action of fibrates, PPAR&ggr; is the receptor for the antidiabetic glitazones. PPAR&agr; is highly expressed in tissues such as liver, muscle, kidney, and heart, where it stimulates the &bgr;-oxidative degradation of fatty acids. PPAR&ggr; is predominantly expressed in adipose tissues, where it promotes adipocyte differentiation and lipid storage. PPAR&bgr;/&dgr; is expressed in a wide range of tissues, and recent findings indicate a role for this receptor in the control of adipogenesis. Pharmacological and gene-targeting studies have demonstrated a physiological role for PPARs in lipid and lipoprotein metabolism. PPAR&agr; controls plasma lipid transport by acting on triglyceride and fatty acid metabolism and by modulating bile acid synthesis and catabolism in the liver. All 3 PPARs regulate macrophage cholesterol homeostasis. By enhancing cholesterol efflux, they stimulate the critical steps of the reverse cholesterol transport pathway. As such, PPARs control plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, PPAR&agr; and PPAR&ggr; regulate the expression of key proteins involved in all stages of atherogenesis, such as monocyte and lymphocyte recruitment to the arterial wall, foam cell formation, vascular inflammation, and thrombosis. Thus, by regulating gene transcription, PPARs modulate the onset and evolution of metabolic disorders predisposing to atherosclerosis and exert direct antiatherogenic actions at the level of the vascular wall.","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":"81794086","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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