Pub Date : 2002-05-01DOI: 10.1161/01.ATV.0000012302.11991.42
E. Tai, S. Demissie, L. Cupples, Dolores Corella, P. W. Wilson, E. J. Schaefer, J. Ordovás
Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the PPARA locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (P =0.0012 and P =0.0004, respectively) and apolipoprotein B in men (P =0.009) and women (P =0.03 after adjustment for age, body mass index, smoking, and use of &bgr;-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the APOE locus and the G allele at the APOC3 3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase LDL cholesterol observed with the L162V PPARA polymorphism.
{"title":"Association Between the PPARA L162V Polymorphism and Plasma Lipid Levels: The Framingham Offspring Study","authors":"E. Tai, S. Demissie, L. Cupples, Dolores Corella, P. W. Wilson, E. J. Schaefer, J. Ordovás","doi":"10.1161/01.ATV.0000012302.11991.42","DOIUrl":"https://doi.org/10.1161/01.ATV.0000012302.11991.42","url":null,"abstract":"Peroxisome proliferator activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation, extracellular lipid metabolism, hemostasis, and inflammation. A L162V polymorphism at the PPARA locus has been associated with alterations in lipid and apolipoprotein concentrations. We studied the association among lipids, lipoproteins, and apolipoproteins and the presence of the L162V polymorphism in 2373 participants (1128 men and 1244 women) in the Framingham Offspring Study. The frequency of the less common allele (V162) was 0.069. The V162 allele was associated with increased serum concentrations of total and LDL cholesterol in men (P =0.0012 and P =0.0004, respectively) and apolipoprotein B in men (P =0.009) and women (P =0.03 after adjustment for age, body mass index, smoking, and use of &bgr;-blockers, diuretics or estrogens). Apolipoprotein (apo) C-III concentrations were higher in carriers of the V162 allele. The association of the L162V polymorphism on LDL cholesterol concentration was greatest in those who also carried the E2 allele at the APOE locus and the G allele at the APOC3 3238C>G polymorphism. This suggests that alterations in triglyceride-rich lipoprotein metabolism may be involved in the generation of the increase LDL cholesterol observed with the L162V PPARA polymorphism.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"31 1","pages":"805-810"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86265153","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.0000015903.02749.71
T. Yamakawa, Shun-ichi Tanaka, Y. Yamakawa, J. Kamei, K. Numaguchi, E. Motley, T. Inagami, S. Eguchi
Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants, N-acetyl-l-cysteine, glutathione monoester, or &agr; -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of c-fos expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.
{"title":"Lysophosphatidylcholine Activates Extracellular Signal-Regulated Kinases 1/2 Through Reactive Oxygen Species in Rat Vascular Smooth Muscle Cells","authors":"T. Yamakawa, Shun-ichi Tanaka, Y. Yamakawa, J. Kamei, K. Numaguchi, E. Motley, T. Inagami, S. Eguchi","doi":"10.1161/01.ATV.0000015903.02749.71","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015903.02749.71","url":null,"abstract":"Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants, N-acetyl-l-cysteine, glutathione monoester, or &agr; -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of c-fos expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"22 1","pages":"752-758"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75399399","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.0000012662.29622.00
F. Jaffer, C. O’Donnell, M. Larson, S. K. Chan, K. Kissinger, Michelle J. Kupka, Carol J. Salton, René M. Botnar, D. Levy, W. Manning
Autopsy data demonstrate a correlation between subclinical aortic atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60±9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal aortic CMR scanning. CMR evidence of aortic atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.
{"title":"Age and Sex Distribution of Subclinical Aortic Atherosclerosis: A Magnetic Resonance Imaging Examination of the Framingham Heart Study","authors":"F. Jaffer, C. O’Donnell, M. Larson, S. K. Chan, K. Kissinger, Michelle J. Kupka, Carol J. Salton, René M. Botnar, D. Levy, W. Manning","doi":"10.1161/01.ATV.0000012662.29622.00","DOIUrl":"https://doi.org/10.1161/01.ATV.0000012662.29622.00","url":null,"abstract":"Autopsy data demonstrate a correlation between subclinical aortic atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60±9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal aortic CMR scanning. CMR evidence of aortic atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"33 1","pages":"849-854"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84636099","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.0000015078.09208.92
A. Chase, M. Bond, M. Crook, A. Newby
Metalloproteinase secretion by macrophages is believed to play a key role in the matrix degradation that underlies atherosclerotic plaque instability and aneurysm formation. We studied the hypothesis that nuclear factor-&kgr;B (NF-&kgr;B), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Adenovirus-mediated gene transfer of the inhibitory NF-&kgr;B subunit, I-&kgr; B&agr;, was achieved into human monocyte-derived macrophages in vitro and into foam cells produced in vivo in cholesterol-fed rabbits. Human macrophages and rabbit foam cells secreted matrix-degrading metalloproteinase (MMP)-9 without further stimulation, and this was not inhibited by I-&kgr;B&agr; (11±16% and 8±10%, respectively;P > 0.05). MMP-1 secretion from human macrophages increased in response to recombinant human CD40 ligand and was inhibited 92±5% by I-&kgr;B&agr; (n=3, P <0.05). Rabbit foam cells secreted MMP-1 and -3 without further stimulation, and this was inhibited 83±12% and 69±11%, respectively, by I-&kgr;B&agr; (n=6 or 7, P <0.001). I-&kgr;B&agr; did not significantly affect the expression or activity of tissue inhibitor of metalloproteinases-1 or -2. Overexpression of I-&kgr;B&agr; inhibited collagenolytic and &bgr;-caseinolytic activity by 42±2% and 41±7%, respectively (n=3, P <0.05). Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-&kgr;B. Because the inhibition of NF-&kgr;B reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas.
巨噬细胞分泌的金属蛋白酶被认为在基质降解中起关键作用，而基质降解是动脉粥样硬化斑块不稳定和动脉瘤形成的基础。我们研究了核因子-&kgr;B (NF-&kgr;B)，一种转录因子，是金属蛋白酶分泌所必需的，因此是药物干预的目标。腺病毒介导的抑制NF-&kgr;B亚基，I-&kgr的基因转移B&agr;在体外转化为人单核细胞来源的巨噬细胞，并在体内转化为胆固醇喂养家兔产生的泡沫细胞。人巨噬细胞和兔泡沫细胞在没有进一步刺激的情况下分泌基质降解金属蛋白酶(MMP)-9，并且这种活性不受I-&kgr;(11±16%、8±10%;P > 0.05)。人巨噬细胞对重组人CD40配体的MMP-1分泌增加，I-&kgr;B&agr;(n=3, P <0.05)。兔泡沫细胞在没有进一步刺激的情况下分泌MMP-1和-3,I-&kgr;B&agr;(n=6或7,P <0.001)。我-&kgr; B&agr;对金属蛋白酶组织抑制剂-1或-2的表达及活性无显著影响。I-&kgr;B&agr过表达;抑制胶原溶解活性和酪蛋白溶解活性分别为42±2%和41±7% (n=3, P <0.05)。体外或体内刺激巨噬细胞分泌MMP-1和MMP-3依赖于NF-&kgr;B的激活。由于抑制NF-&kgr;B可降低蛋白水解活性，因此它似乎是治疗不稳定动脉粥样硬化的一个有吸引力的药理靶点。
{"title":"Role of Nuclear Factor-&kgr;B Activation in Metalloproteinase-1, -3, and -9 Secretion by Human Macrophages In Vitro and Rabbit Foam Cells Produced In Vivo","authors":"A. Chase, M. Bond, M. Crook, A. Newby","doi":"10.1161/01.ATV.0000015078.09208.92","DOIUrl":"https://doi.org/10.1161/01.ATV.0000015078.09208.92","url":null,"abstract":"Metalloproteinase secretion by macrophages is believed to play a key role in the matrix degradation that underlies atherosclerotic plaque instability and aneurysm formation. We studied the hypothesis that nuclear factor-&kgr;B (NF-&kgr;B), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Adenovirus-mediated gene transfer of the inhibitory NF-&kgr;B subunit, I-&kgr; B&agr;, was achieved into human monocyte-derived macrophages in vitro and into foam cells produced in vivo in cholesterol-fed rabbits. Human macrophages and rabbit foam cells secreted matrix-degrading metalloproteinase (MMP)-9 without further stimulation, and this was not inhibited by I-&kgr;B&agr; (11±16% and 8±10%, respectively;P > 0.05). MMP-1 secretion from human macrophages increased in response to recombinant human CD40 ligand and was inhibited 92±5% by I-&kgr;B&agr; (n=3, P <0.05). Rabbit foam cells secreted MMP-1 and -3 without further stimulation, and this was inhibited 83±12% and 69±11%, respectively, by I-&kgr;B&agr; (n=6 or 7, P <0.001). I-&kgr;B&agr; did not significantly affect the expression or activity of tissue inhibitor of metalloproteinases-1 or -2. Overexpression of I-&kgr;B&agr; inhibited collagenolytic and &bgr;-caseinolytic activity by 42±2% and 41±7%, respectively (n=3, P <0.05). Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-&kgr;B. Because the inhibition of NF-&kgr;B reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"97 7 1","pages":"765-771"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88647983","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.0000016248.51577.1F
Jian Wang, D. Dudley, Xing-li Wang
The T–786C promoter and 27-bp repeat intron 4 polymorphisms in the endothelial NO synthase (eNOS) gene have been inconsistently associated with various eNOS-related phenotypic changes. We explored molecular mechanisms underlying the inconsistency. We constructed pGL3 luciferase reporter vectors by inserting an eNOS promoter fragment containing either T or C nucleotide at −786 bp at the 5′ end of the luciferase coding region and eNOS intron 4 containing either 5× or 4×27-bp repeats at the 3′ end of the luciferase gene. The transcription efficiency in the T promoter was lower than in the C promoter (15.7±1.0% vs 83.3±5.8%, P <0.01 when 5×27-bp was an enhancer and 37.6±4.7% vs 58.9±7.5%, P <0.01 when 4×27bp was an enhancer). Although cigarette smoking extracts treatment increased the transcription efficiency significantly in the T promoter (1.7-fold, P <0.01), it reduced the C promoter efficiency (by 10% to 15%). A mobility shift assay revealed positive binding of the 27-bp repeat fragment with endothelial cell nuclear protein extracts. Our study demonstrates a cis-acting role of the 27-bp repeats in eNOS promoter function and a haplotype-specific expression pattern determined by DNA variants at −786 bp and intron 4 of the eNOS gene that is also modifiable by cigarette smoking.
{"title":"Haplotype-Specific Effects on Endothelial NO Synthase Promoter Efficiency: Modifiable by Cigarette Smoking","authors":"Jian Wang, D. Dudley, Xing-li Wang","doi":"10.1161/01.ATV.0000016248.51577.1F","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016248.51577.1F","url":null,"abstract":"The T–786C promoter and 27-bp repeat intron 4 polymorphisms in the endothelial NO synthase (eNOS) gene have been inconsistently associated with various eNOS-related phenotypic changes. We explored molecular mechanisms underlying the inconsistency. We constructed pGL3 luciferase reporter vectors by inserting an eNOS promoter fragment containing either T or C nucleotide at −786 bp at the 5′ end of the luciferase coding region and eNOS intron 4 containing either 5× or 4×27-bp repeats at the 3′ end of the luciferase gene. The transcription efficiency in the T promoter was lower than in the C promoter (15.7±1.0% vs 83.3±5.8%, P <0.01 when 5×27-bp was an enhancer and 37.6±4.7% vs 58.9±7.5%, P <0.01 when 4×27bp was an enhancer). Although cigarette smoking extracts treatment increased the transcription efficiency significantly in the T promoter (1.7-fold, P <0.01), it reduced the C promoter efficiency (by 10% to 15%). A mobility shift assay revealed positive binding of the 27-bp repeat fragment with endothelial cell nuclear protein extracts. Our study demonstrates a cis-acting role of the 27-bp repeats in eNOS promoter function and a haplotype-specific expression pattern determined by DNA variants at −786 bp and intron 4 of the eNOS gene that is also modifiable by cigarette smoking.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"2 1","pages":"e1-e4"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81047599","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.0000016046.94521.68
D. Alber, P. Vallance, K. Powell
Viral and bacterial infectious agents have been implicated in the etiology of atherosclerosis. We have previously shown that a &ggr;-herpesvirus can accelerate atherosclerosis in the apolipoprotein E–deficient (apoE−/−) mouse. To address whether a virally induced systemic immune response is sufficient to trigger enhanced atheroma formation, we infected apoE−/− mice with murine &ggr;-herpesvirus-68 (MHV-68) or herpes simplex virus-1 (HSV-1). In this study, we show that both viruses were able to induce a cell-mediated and humoral immune response in the apoE−/− mouse, which was sustained over a period of 24 weeks. Although intranasal or intraperitoneal infection with MHV-68 induced similar levels of virus-specific IgG1 and IgG2a antibodies in the serum of apoE−/− mice, those infected with HSV-1 showed higher anti–HSV-1 IgG2a compared with IgG1 antibody levels. In addition, viral message was not detected in the aortas of HSV-1–infected animals, whereas we have shown previously that MHV-68 mRNA can be detected in the aortas of infected mice as early as 5 days after infection. Compared with control mice, apoE−/− mice infected with MHV-68 showed accelerated atherosclerosis, whereas mice infected with HSV-1 did not. These data indicate that a systemic immune response to any particular infectious agent is insufficient to induce enhanced atherosclerosis in the apoE−/− mouse and point to specific infections or immune mechanisms that might be essential for virally enhanced atherogenesis.
{"title":"Enhanced Atherogenesis Is Not an Obligatory Response to Systemic Herpesvirus Infection in the ApoE-Deficient Mouse: Comparison of Murine &ggr;-Herpesvirus-68 and Herpes Simplex Virus-1","authors":"D. Alber, P. Vallance, K. Powell","doi":"10.1161/01.ATV.0000016046.94521.68","DOIUrl":"https://doi.org/10.1161/01.ATV.0000016046.94521.68","url":null,"abstract":"Viral and bacterial infectious agents have been implicated in the etiology of atherosclerosis. We have previously shown that a &ggr;-herpesvirus can accelerate atherosclerosis in the apolipoprotein E–deficient (apoE−/−) mouse. To address whether a virally induced systemic immune response is sufficient to trigger enhanced atheroma formation, we infected apoE−/− mice with murine &ggr;-herpesvirus-68 (MHV-68) or herpes simplex virus-1 (HSV-1). In this study, we show that both viruses were able to induce a cell-mediated and humoral immune response in the apoE−/− mouse, which was sustained over a period of 24 weeks. Although intranasal or intraperitoneal infection with MHV-68 induced similar levels of virus-specific IgG1 and IgG2a antibodies in the serum of apoE−/− mice, those infected with HSV-1 showed higher anti–HSV-1 IgG2a compared with IgG1 antibody levels. In addition, viral message was not detected in the aortas of HSV-1–infected animals, whereas we have shown previously that MHV-68 mRNA can be detected in the aortas of infected mice as early as 5 days after infection. Compared with control mice, apoE−/− mice infected with MHV-68 showed accelerated atherosclerosis, whereas mice infected with HSV-1 did not. These data indicate that a systemic immune response to any particular infectious agent is insufficient to induce enhanced atherosclerosis in the apoE−/− mouse and point to specific infections or immune mechanisms that might be essential for virally enhanced atherogenesis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"107 1","pages":"793-798"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72875257","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 : 2002-04-11DOI: 10.1161/01.ATV.0000018304.30943.06
J. Millar, C. Maugeais, I. Fuki, D. Rader
The low density lipoprotein (LDL) receptor is well known for its role in mediating the removal of apolipoprotein B (apoB)-containing lipoproteins from plasma. Results from in vitro studies in primary mouse hepatocytes suggest that the LDL receptor may also have a role in the regulation of very low density lipoprotein (VLDL) production. We conducted in vivo experiments using LDLR −/−, LDLR +/−, and wild-type mice (LDLR indicates LDL receptor gene) in which the production rate of VLDL was measured after the injection of [35S]methionine and the lipase inhibitor Triton WR1339. Despite the fact that LDLR −/− mice had a 3.7-fold higher total cholesterol level and a 2.1-fold higher triglyceride level than those of the wild-type mice, there was no difference in the production rate of VLDL triglyceride or VLDL apoB between these groups of animals. Experiments were also conducted in apobec1 −/− mice, which make only apoB-100, the form of apoB that binds to the LDL receptor. Interestingly, the apobec1 −/− mice had a significantly higher production rate of apoB than did the wild-type mice. However, despite significant differences in total cholesterol and triglyceride levels, there was no difference in the production rate of total or VLDL triglyceride or VLDL apoB between LDLR −/− and LDLR +/− mice on an apobec1 −/− background. These results indicate that the LDL receptor has no effect on the production rate of VLDL triglyceride or apoB in vivo in mice.
{"title":"Normal Production Rate of Apolipoprotein B in LDL Receptor–Deficient Mice","authors":"J. Millar, C. Maugeais, I. Fuki, D. Rader","doi":"10.1161/01.ATV.0000018304.30943.06","DOIUrl":"https://doi.org/10.1161/01.ATV.0000018304.30943.06","url":null,"abstract":"The low density lipoprotein (LDL) receptor is well known for its role in mediating the removal of apolipoprotein B (apoB)-containing lipoproteins from plasma. Results from in vitro studies in primary mouse hepatocytes suggest that the LDL receptor may also have a role in the regulation of very low density lipoprotein (VLDL) production. We conducted in vivo experiments using LDLR −/−, LDLR +/−, and wild-type mice (LDLR indicates LDL receptor gene) in which the production rate of VLDL was measured after the injection of [35S]methionine and the lipase inhibitor Triton WR1339. Despite the fact that LDLR −/− mice had a 3.7-fold higher total cholesterol level and a 2.1-fold higher triglyceride level than those of the wild-type mice, there was no difference in the production rate of VLDL triglyceride or VLDL apoB between these groups of animals. Experiments were also conducted in apobec1 −/− mice, which make only apoB-100, the form of apoB that binds to the LDL receptor. Interestingly, the apobec1 −/− mice had a significantly higher production rate of apoB than did the wild-type mice. However, despite significant differences in total cholesterol and triglyceride levels, there was no difference in the production rate of total or VLDL triglyceride or VLDL apoB between LDLR −/− and LDLR +/− mice on an apobec1 −/− background. These results indicate that the LDL receptor has no effect on the production rate of VLDL triglyceride or apoB in vivo in mice.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"2016 1","pages":"989-994"},"PeriodicalIF":0.0,"publicationDate":"2002-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86630837","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}
Elevated levels of tissue-type plasminogen activator antigen (tPA), fibrinogen, and fibrin D-dimer predict coronary artery disease (CAD) events and stroke. These factors, possibly in association with insulin resistance, may be important in families in which CAD has become clinically apparent at a premature age. From 125 patients with angiographically confirmed, premature CAD, 175 healthy male relatives (age ≤65 years) were identified. One hundred seventy-five healthy volunteers of similar age and without any family history of CAD were recruited. There were no differences between relatives and controls in terms of conventional CAD risk factors, cigarette smoking, alcohol consumption, or cardiorespiratory fitness. Estimated insulin resistance and plasminogen activator inhibitor 1 levels were not increased in relatives. Fibrin D-dimer, tPA, and fibrinogen levels were elevated in relatives compared with controls, 55 (52 to 58) ng/mL versus 49 (45 to 53) ng/mL, P <0.01, for D-dimer; 8.0 (7.5 to 8.6) ng/mL versus 5.6 (5.2 to 6.1) ng/mL, P <0.001, for tPA; and 3.0 (2.9 to 3.1) g/L versus 2.8 (2.7 to 2.9) g/L, P <0.05, for fibrinogen. These differences remained after adjustment for correlates, including fibrinogen, age for D-dimer, and features of the insulin resistance syndrome for tPA. tPA and D-dimer levels are elevated in the healthy, male, first-degree relatives of patients with premature CAD. This association is independent of potential confounding factors.
{"title":"Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease","authors":"J. Mills, M. Mansfield, P. Grant","doi":"10.1161/HQ0402.105902","DOIUrl":"https://doi.org/10.1161/HQ0402.105902","url":null,"abstract":"Elevated levels of tissue-type plasminogen activator antigen (tPA), fibrinogen, and fibrin D-dimer predict coronary artery disease (CAD) events and stroke. These factors, possibly in association with insulin resistance, may be important in families in which CAD has become clinically apparent at a premature age. From 125 patients with angiographically confirmed, premature CAD, 175 healthy male relatives (age ≤65 years) were identified. One hundred seventy-five healthy volunteers of similar age and without any family history of CAD were recruited. There were no differences between relatives and controls in terms of conventional CAD risk factors, cigarette smoking, alcohol consumption, or cardiorespiratory fitness. Estimated insulin resistance and plasminogen activator inhibitor 1 levels were not increased in relatives. Fibrin D-dimer, tPA, and fibrinogen levels were elevated in relatives compared with controls, 55 (52 to 58) ng/mL versus 49 (45 to 53) ng/mL, P <0.01, for D-dimer; 8.0 (7.5 to 8.6) ng/mL versus 5.6 (5.2 to 6.1) ng/mL, P <0.001, for tPA; and 3.0 (2.9 to 3.1) g/L versus 2.8 (2.7 to 2.9) g/L, P <0.05, for fibrinogen. These differences remained after adjustment for correlates, including fibrinogen, age for D-dimer, and features of the insulin resistance syndrome for tPA. tPA and D-dimer levels are elevated in the healthy, male, first-degree relatives of patients with premature CAD. This association is independent of potential confounding factors.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"30 1","pages":"704-709"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80609591","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 : 2002-04-01DOI: 10.1161/01.ATV.0000012804.63152.60
F. Böhm, G. Ahlborg, B. Johansson, L. Hansson, J. Pernow
Endothelin (ET)-1 causes vasoconstriction via ETA and ETB receptors located on vascular smooth muscle cells and vasodilatation via ETB receptors on endothelial cells. Studies in vitro indicate an upregulation of ETB receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ETB receptor antagonist BQ788 evoked a significant increase in FBF (31±13%) in the patients, whereas a 20±9% reduction was observed in the control subjects. The ETA receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102±25%) in the patients compared with no effect in the control subjects (−3±9%, P <0.001 versus patients). The ETA receptor antagonist BQ123 increased FBF to a similar degree in patients (39±11%) as in control subjects (41±11%). The increase in FBF evoked by selective ETA receptor blockade was significantly (P <0.05) less than that evoked by combined ETA/ETB receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1–mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ETB-mediated vasoconstriction.
{"title":"Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis","authors":"F. Böhm, G. Ahlborg, B. Johansson, L. Hansson, J. Pernow","doi":"10.1161/01.ATV.0000012804.63152.60","DOIUrl":"https://doi.org/10.1161/01.ATV.0000012804.63152.60","url":null,"abstract":"Endothelin (ET)-1 causes vasoconstriction via ETA and ETB receptors located on vascular smooth muscle cells and vasodilatation via ETB receptors on endothelial cells. Studies in vitro indicate an upregulation of ETB receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ETB receptor antagonist BQ788 evoked a significant increase in FBF (31±13%) in the patients, whereas a 20±9% reduction was observed in the control subjects. The ETA receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102±25%) in the patients compared with no effect in the control subjects (−3±9%, P <0.001 versus patients). The ETA receptor antagonist BQ123 increased FBF to a similar degree in patients (39±11%) as in control subjects (41±11%). The increase in FBF evoked by selective ETA receptor blockade was significantly (P <0.05) less than that evoked by combined ETA/ETB receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1–mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ETB-mediated vasoconstriction.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"16 1","pages":"674-679"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89898105","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 : 2002-04-01DOI: 10.1161/01.ATV.0000014221.30108.08
M. Silverman, R. Tumuluri, Mishel Davis, Gladys E. Lopez, J. Rosenbaum, P. Lelkes
Elevated plasma homocysteine is an independent risk factor for atherosclerosis. We hypothesized that homocysteine enhances monocyte/human aortic endothelial cell (HAEC) interactions, a pivotal early event in atherogenesis, by upregulating endothelial adhesion molecules. After incubation of cultured HAECs with reduced dl-homocysteine for up to 24 hours, adhesion of human monocytes to homocysteine-stimulated HAECs was significantly upregulated in a time- and dose-dependent fashion. Pretreatment of HAECs with 100 &mgr;mol/L homocysteine caused a 4.5-fold increase in the adhesion of normal human monocytes (P <0.001). Similarly, adhesion of monocytic U937 cells was maximally elevated by 3.5-fold at 100 &mgr;mol/L homocysteine (P <0.001). In support of our hypothesis, vascular cell adhesion molecule (VCAM)-1 mRNA expression increased 5-fold in HAECs after 3 hours of treatment with 100 &mgr; mol/L homocysteine, as assessed by quantitative reverse transcription– polymerase chain reaction. Neutralizing antibody studies confirmed the involvement of VCAM-1 in mediating monocyte adhesion to homocysteine-stimulated HAECs. Coincubation of HAECs with homocysteine and tumor necrosis factor-&agr; synergistically elevated monocyte adhesion as well as VCAM-1 protein expression, with the latter evaluated by flow cytometry. Preincubation of HAECs with cyclooxygenase inhibitors completely abrogated homocysteine-induced monocyte adhesion, whereas scavenging reactive oxygen species and the elevation of NO caused partial inhibition only. These data support the notion that the proinflammatory effects of homocysteine may have important implications in atherogenesis.
{"title":"Homocysteine Upregulates Vascular Cell Adhesion Molecule-1 Expression in Cultured Human Aortic Endothelial Cells and Enhances Monocyte Adhesion","authors":"M. Silverman, R. Tumuluri, Mishel Davis, Gladys E. Lopez, J. Rosenbaum, P. Lelkes","doi":"10.1161/01.ATV.0000014221.30108.08","DOIUrl":"https://doi.org/10.1161/01.ATV.0000014221.30108.08","url":null,"abstract":"Elevated plasma homocysteine is an independent risk factor for atherosclerosis. We hypothesized that homocysteine enhances monocyte/human aortic endothelial cell (HAEC) interactions, a pivotal early event in atherogenesis, by upregulating endothelial adhesion molecules. After incubation of cultured HAECs with reduced dl-homocysteine for up to 24 hours, adhesion of human monocytes to homocysteine-stimulated HAECs was significantly upregulated in a time- and dose-dependent fashion. Pretreatment of HAECs with 100 &mgr;mol/L homocysteine caused a 4.5-fold increase in the adhesion of normal human monocytes (P <0.001). Similarly, adhesion of monocytic U937 cells was maximally elevated by 3.5-fold at 100 &mgr;mol/L homocysteine (P <0.001). In support of our hypothesis, vascular cell adhesion molecule (VCAM)-1 mRNA expression increased 5-fold in HAECs after 3 hours of treatment with 100 &mgr; mol/L homocysteine, as assessed by quantitative reverse transcription– polymerase chain reaction. Neutralizing antibody studies confirmed the involvement of VCAM-1 in mediating monocyte adhesion to homocysteine-stimulated HAECs. Coincubation of HAECs with homocysteine and tumor necrosis factor-&agr; synergistically elevated monocyte adhesion as well as VCAM-1 protein expression, with the latter evaluated by flow cytometry. Preincubation of HAECs with cyclooxygenase inhibitors completely abrogated homocysteine-induced monocyte adhesion, whereas scavenging reactive oxygen species and the elevation of NO caused partial inhibition only. These data support the notion that the proinflammatory effects of homocysteine may have important implications in atherogenesis.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"48 1","pages":"587-592"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74722612","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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