Pub Date : 2002-07-01DOI: 10.1161/01.ATV.0000022695.22369.BE
A. Tiran, H. Gruber, W. F. Graier, A. Wagner, E. B. van Leeuwen, B. Tiran
Objective—Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-&kgr;B, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae–induced NF-&kgr;B activation, interleukin expression, and bacterial development in cultured human endothelial cells. Methods and Results—Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-&kgr;B inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-&kgr;B was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of the C pneumoniae–induced activation of NF-&kgr;B by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-&kgr;B gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation. Conclusions—These data provide evidence that NF-&kgr;B–mediated gene activation represents a crucial step in the developmental cycle of C pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition of C pneumoniae–induced NF-&kgr;B activation, which might account for some of the cardioprotective activity of aspirin.
{"title":"Aspirin Inhibits Chlamydia pneumoniae–Induced Nuclear Factor-&kgr;B Activation, Cytokine Expression, and Bacterial Development in Human Endothelial Cells","authors":"A. Tiran, H. Gruber, W. F. Graier, A. Wagner, E. B. van Leeuwen, B. Tiran","doi":"10.1161/01.ATV.0000022695.22369.BE","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022695.22369.BE","url":null,"abstract":"Objective—Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-&kgr;B, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae–induced NF-&kgr;B activation, interleukin expression, and bacterial development in cultured human endothelial cells. Methods and Results—Aspirin, its metabolite salicylic acid, and 2 other unrelated NF-&kgr;B inhibitors showed a strong concentration-dependent inhibitory effect on chlamydial growth, indicated by the reduction of bacterial inclusions and the titer of infectious progeny. Involvement of the transcription factor NF-&kgr;B was confirmed by electrophoretic mobility shift assay and by transfection experiments with appropriate decoy oligodeoxynucleotides. Attenuation of the C pneumoniae–induced activation of NF-&kgr;B by aspirin also reduced the secretion of interleukin-6 and interleukin-8, indicating efficient inhibition of NF-&kgr;B gene expression. Reduction of chlamydial growth was not caused by apoptosis of the host cell, as determined by monitoring characteristic chromatin condensation. Conclusions—These data provide evidence that NF-&kgr;B–mediated gene activation represents a crucial step in the developmental cycle of C pneumoniae. Aspirin exerts an anti-chlamydial effect that is due to the inhibition of C pneumoniae–induced NF-&kgr;B activation, which might account for some of the cardioprotective activity of aspirin.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":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":"90733901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-07-01DOI: 10.1161/01.ATV.0000022167.80130.A6
M. Ng, Peter Y. Liu, A. J. Williams, S. Nakhla, L. P. Ly, David Handelsman, D. Celermajer
Objective—Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men. Methods and Results—Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged >60 years with partial androgen deficiency (serum testosterone levels <15 nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 &mgr;g twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo (P >0.3 in both studies). Conclusions—Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.
{"title":"Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men","authors":"M. Ng, Peter Y. Liu, A. J. Williams, S. Nakhla, L. P. Ly, David Handelsman, D. Celermajer","doi":"10.1161/01.ATV.0000022167.80130.A6","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022167.80130.A6","url":null,"abstract":"Objective—Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men. Methods and Results—Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged >60 years with partial androgen deficiency (serum testosterone levels <15 nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 &mgr;g twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo (P >0.3 in both studies). Conclusions—Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.","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":"88333126","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.0000022600.61391.A5
S. von Bahr, T. Movin, N. Papadogiannakis, I. Pikuleva, Per Rönnow, U. Diczfalusy, I. Björkhem
Objective—Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both cholestanol and cholesterol, with a cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. Methods and Results—Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained cholestanol, with a cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and cholestanol. After loading of macrophages with labeled cholesterol and cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of cholestanol compared with cholesterol. Conclusion—The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and cholestanol from tendons.
{"title":"Mechanism of Accumulation of Cholesterol and Cholestanol in Tendons and the Role of Sterol 27-hydroxylase (CYP27A1)","authors":"S. von Bahr, T. Movin, N. Papadogiannakis, I. Pikuleva, Per Rönnow, U. Diczfalusy, I. Björkhem","doi":"10.1161/01.ATV.0000022600.61391.A5","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022600.61391.A5","url":null,"abstract":"Objective—Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both cholestanol and cholesterol, with a cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. Methods and Results—Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained cholestanol, with a cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and cholestanol. After loading of macrophages with labeled cholesterol and cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of cholestanol compared with cholesterol. Conclusion—The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and cholestanol from tendons.","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":"84371664","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.0000021411.53577.1C
T. Major, L. Liang, Xiao-Dong Lu, W. Rosebury, T. Bocan
Objective—Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell–derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)–differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma. Methods and Results—After 10 days of GM-CSF–induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF–differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF–differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions. Conclusions—Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.
{"title":"Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma","authors":"T. Major, L. Liang, Xiao-Dong Lu, W. Rosebury, T. Bocan","doi":"10.1161/01.ATV.0000021411.53577.1C","DOIUrl":"https://doi.org/10.1161/01.ATV.0000021411.53577.1C","url":null,"abstract":"Objective—Because extracellular matrix metalloproteinase inducer (EMMPRIN), a tumor cell–derived protein, induces matrix metalloproteinases (MMPs) in fibroblasts and because MMPs are important in atheroma formation, we investigated if EMMPRIN was expressed in granulocyte/macrophage-colony stimulating factor (GM-CSF)–differentiated human peripheral blood monocytes (HPBM) and macrophage foam cells. In addition, EMMPRIN was studied for its expression in human atheroma. Methods and Results—After 10 days of GM-CSF–induced monocyte differentiation, EMMPRIN mRNA increased 5- to 8-fold relative to undifferentiated monocytes. GM-CSF treatment of HPBM revealed that both EMMPRIN mRNA and protein were upregulated by day 2 over undifferentiated monocytes. GM-CSF–differentiated HPBM showed characteristic macrophage phenotype by showing increases in pancake-like morphology and increases in biochemical markers such as apolipoprotein E, MMP-9, and cholesterol ester (CE). While acetylated LDL treatment of the 10-day GM-CSF–differentiated HPBM increased CE mass 13- to 321-fold, EMMPRIN expression was unchanged relative to nonlipid-loaded macrophages. In human coronary atherosclerotic samples, EMMPRIN was observed in CD68(+) macrophage-rich areas as well as areas of MMP-9 expressions. Conclusions—Based on these data, we conclude that monocyte differentiation induces EMMPRIN expression, CE enrichment of foam cells has no further effect on EMMPRIN expression, and EMMPRIN is present in human atheroma. Therefore, EMMPRIN may play a role in atherosclerosis development.","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":"90425895","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.0000021955.23461.CD
C. Jen, Hung-Pin Chan, H. Chen
Objective—This study was to investigate the effects of chronic exercise on vasodilatation and endothelial intracellular calcium (EC [Ca2+]i) signaling in atherosclerotic animals. Methods and Results—For 8 weeks, male New Zealand White rabbits were fed rabbit chow with or without the addition of 2% cholesterol. They were further divided into control and exercise groups. Animals in the exercise groups ran on a leveled treadmill at 0.88 km/h for 10 to 60 minutes gradually for 5 days per week for a total of 8 weeks. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. PE-precontracted vessel specimens were exposed to acetylcholine (ACh). The EC [Ca2+]i elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope equipped with a ratio-imaging capability. Our results showed the following: (1) high cholesterol diet feeding caused lipid deposition on vascular surface, reduced the ACh-evoked EC [Ca2+]i elevation, and impaired endothelium-dependent and endothelium-independent vascular responses, but chronic exercise had the opposite effects; (2) ACh-induced vasorelaxation was associated with EC [Ca2+]i elevation in all groups; and (3) vasorelaxation at high levels of EC [Ca2+]i elevation decreased in hypercholesterolemia. Conclusions—Our data suggest that hypercholesterolemia induces vascular structural changes and impairs EC [Ca2+]i signaling and vasodilatation, whereas chronic exercise partially reverses these adverse effects.
{"title":"Chronic Exercise Improves Endothelial Calcium Signaling and Vasodilatation in Hypercholesterolemic Rabbit Femoral Artery","authors":"C. Jen, Hung-Pin Chan, H. Chen","doi":"10.1161/01.ATV.0000021955.23461.CD","DOIUrl":"https://doi.org/10.1161/01.ATV.0000021955.23461.CD","url":null,"abstract":"Objective—This study was to investigate the effects of chronic exercise on vasodilatation and endothelial intracellular calcium (EC [Ca2+]i) signaling in atherosclerotic animals. Methods and Results—For 8 weeks, male New Zealand White rabbits were fed rabbit chow with or without the addition of 2% cholesterol. They were further divided into control and exercise groups. Animals in the exercise groups ran on a leveled treadmill at 0.88 km/h for 10 to 60 minutes gradually for 5 days per week for a total of 8 weeks. At the end of experiments, femoral arteries were dissected, loaded with fura 2-AM, and mounted in a tissue flow chamber. PE-precontracted vessel specimens were exposed to acetylcholine (ACh). The EC [Ca2+]i elevation and vasorelaxation were determined simultaneously under an epifluorescence microscope equipped with a ratio-imaging capability. Our results showed the following: (1) high cholesterol diet feeding caused lipid deposition on vascular surface, reduced the ACh-evoked EC [Ca2+]i elevation, and impaired endothelium-dependent and endothelium-independent vascular responses, but chronic exercise had the opposite effects; (2) ACh-induced vasorelaxation was associated with EC [Ca2+]i elevation in all groups; and (3) vasorelaxation at high levels of EC [Ca2+]i elevation decreased in hypercholesterolemia. Conclusions—Our data suggest that hypercholesterolemia induces vascular structural changes and impairs EC [Ca2+]i signaling and vasodilatation, whereas chronic exercise partially reverses these adverse effects.","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":"89961137","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.0000024566.57589.2E
M. Brousseau, J. O’Connor, J. Ordovás, D. Collins, J. Otvos, T. Massov, J. Mcnamara, H. Rubins, S. Robins, E. Schaefer
Objective—We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) Taq IB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. Methods and Results—We tested for associations between the CETP Taq IB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (≤40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (−27%, P <0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P <0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6±4.8 mg/dL), followed by B1B2 men (32.0±5.3 mg/dL), and, last, by B1B1 men (30.9±4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (−34%, P =0.006). CETP Taq IB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P =0.08). Conclusions—Our data demonstrate that in men with CHD and HDL deficiency, the CETP Taq I B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.
{"title":"Cholesteryl Ester Transfer Protein Taq I B2B2 Genotype Is Associated With Higher HDL Cholesterol Levels and Lower Risk of Coronary Heart Disease End Points in Men With HDL Deficiency: Veterans Affairs HDL Cholesterol Intervention Trial","authors":"M. Brousseau, J. O’Connor, J. Ordovás, D. Collins, J. Otvos, T. Massov, J. Mcnamara, H. Rubins, S. Robins, E. Schaefer","doi":"10.1161/01.ATV.0000024566.57589.2E","DOIUrl":"https://doi.org/10.1161/01.ATV.0000024566.57589.2E","url":null,"abstract":"Objective—We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) Taq IB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. Methods and Results—We tested for associations between the CETP Taq IB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (≤40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (−27%, P <0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P <0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6±4.8 mg/dL), followed by B1B2 men (32.0±5.3 mg/dL), and, last, by B1B1 men (30.9±4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (−34%, P =0.006). CETP Taq IB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P =0.08). Conclusions—Our data demonstrate that in men with CHD and HDL deficiency, the CETP Taq I B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78819648","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.0000021150.63480.CD
J. Hulthe, B. Fagerberg
Objective—Circulating oxidized LDL (Ox-LDL) is associated with clinical manifestations of atherosclerosis. However, no previous study has examined the relationship between subclinical atherosclerosis and Ox-LDL. The aims of the present study were to investigate the relationship between clinically silent ultrasound-assessed atherosclerotic changes in the carotid and femoral arteries and Ox-LDL and to explore the relationship between Ox-LDL, C-reactive protein, and the inflammatory cytokines interleukin-6 and tumor necrosis factor-&agr;. Methods and Results—The study group (n=391) consisted of clinically healthy, 58-year-old men recruited from the general population. Ox-LDL was measured by using a specific monoclonal antibody, mAb-4E6. The results showed that Ox-LDL was related to intima-media thickness and plaque occurrence in the carotid and femoral arteries. In addition, Ox-LDL was associated with tumor necrosis factor-&agr; and C-reactive protein. Circulating Ox-LDL was also associated with LDL cholesterol but not with blood pressure or smoking. When adjusting for other risk factors, both LDL cholesterol and Ox-LDL seemed to be independent predictors of plaque occurrence in the carotid and femoral arteries (odds ratios for quintile 5 versus quintile 1 were 2.17, P =0.049 and 2.25, P =0.050, for LDL cholesterol and Ox-LDL, respectively). Conclusions—Ox-LDL was associated with both subclinical atherosclerosis and inflammatory variables, supporting the concept that oxidatively modified LDL may play a major role in atherosclerosis development, although no causality can be shown in this cross-sectional study.
{"title":"Circulating Oxidized LDL Is Associated With Subclinical Atherosclerosis Development and Inflammatory Cytokines (AIR Study)","authors":"J. Hulthe, B. Fagerberg","doi":"10.1161/01.ATV.0000021150.63480.CD","DOIUrl":"https://doi.org/10.1161/01.ATV.0000021150.63480.CD","url":null,"abstract":"Objective—Circulating oxidized LDL (Ox-LDL) is associated with clinical manifestations of atherosclerosis. However, no previous study has examined the relationship between subclinical atherosclerosis and Ox-LDL. The aims of the present study were to investigate the relationship between clinically silent ultrasound-assessed atherosclerotic changes in the carotid and femoral arteries and Ox-LDL and to explore the relationship between Ox-LDL, C-reactive protein, and the inflammatory cytokines interleukin-6 and tumor necrosis factor-&agr;. Methods and Results—The study group (n=391) consisted of clinically healthy, 58-year-old men recruited from the general population. Ox-LDL was measured by using a specific monoclonal antibody, mAb-4E6. The results showed that Ox-LDL was related to intima-media thickness and plaque occurrence in the carotid and femoral arteries. In addition, Ox-LDL was associated with tumor necrosis factor-&agr; and C-reactive protein. Circulating Ox-LDL was also associated with LDL cholesterol but not with blood pressure or smoking. When adjusting for other risk factors, both LDL cholesterol and Ox-LDL seemed to be independent predictors of plaque occurrence in the carotid and femoral arteries (odds ratios for quintile 5 versus quintile 1 were 2.17, P =0.049 and 2.25, P =0.050, for LDL cholesterol and Ox-LDL, respectively). Conclusions—Ox-LDL was associated with both subclinical atherosclerosis and inflammatory variables, supporting the concept that oxidatively modified LDL may play a major role in atherosclerosis development, although no causality can be shown in this cross-sectional study.","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":"79059469","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.0000022850.59845.E0
G. Luc, J. Bard, J. Ferrières, A. Evans, P. Amouyel, D. Arveiler, J. Fruchart, P. Ducimetiere
Objective—We have examined the association between the incidence of coronary heart disease (CHD) and plasma high density lipoprotein (HDL) cholesterol, apolipoprotein A-I (apoA-I), and 2 HDL fractions, lipoprotein A-I and lipoprotein A-I:A-II. Methods and Results—These parameters were measured in subjects recruited in France and in Northern Ireland in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a prospective cohort study. Among the subjects free of CHD on entry, 176 in France and 113 in Northern Ireland suffered an ischemic attack (CHD patients) during the 5-year follow-up, whereas 6612 French and 2172 Northern Irish men showed no CHD symptoms (CHD-free subjects). All 4 HDL parameter levels were lower in CHD patients than in CHD-free subjects. After the cohort was divided into quintiles based on the distribution of HDL parameter levels, a significant (P <0.0001) linear increase in relative risk was observed for each HDL parameter level. However, regression logistic analyses showed that apoA-I was the strongest predictor (more powerful than HDL cholesterol) and that lipoprotein A-I and lipoprotein A-I:A-II did not supplement apoA-I in predicting CHD. Conclusions—Among the parameters related to HDL, apoA-I appears to be the strongest independent risk factor.
{"title":"Value of HDL Cholesterol, Apolipoprotein A-I, Lipoprotein A-I, and Lipoprotein A-I/A-II in Prediction of Coronary Heart Disease: The PRIME Study","authors":"G. Luc, J. Bard, J. Ferrières, A. Evans, P. Amouyel, D. Arveiler, J. Fruchart, P. Ducimetiere","doi":"10.1161/01.ATV.0000022850.59845.E0","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022850.59845.E0","url":null,"abstract":"Objective—We have examined the association between the incidence of coronary heart disease (CHD) and plasma high density lipoprotein (HDL) cholesterol, apolipoprotein A-I (apoA-I), and 2 HDL fractions, lipoprotein A-I and lipoprotein A-I:A-II. Methods and Results—These parameters were measured in subjects recruited in France and in Northern Ireland in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a prospective cohort study. Among the subjects free of CHD on entry, 176 in France and 113 in Northern Ireland suffered an ischemic attack (CHD patients) during the 5-year follow-up, whereas 6612 French and 2172 Northern Irish men showed no CHD symptoms (CHD-free subjects). All 4 HDL parameter levels were lower in CHD patients than in CHD-free subjects. After the cohort was divided into quintiles based on the distribution of HDL parameter levels, a significant (P <0.0001) linear increase in relative risk was observed for each HDL parameter level. However, regression logistic analyses showed that apoA-I was the strongest predictor (more powerful than HDL cholesterol) and that lipoprotein A-I and lipoprotein A-I:A-II did not supplement apoA-I in predicting CHD. Conclusions—Among the parameters related to HDL, apoA-I appears to be the strongest independent risk factor.","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":"85372547","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.0000022878.37277.EC
N. Seki, N. Hashimoto, Yoshifumi Suzuki, S. Mori, K. Amano, Y. Saito
Objective—Src homology 2–containing phosphotyrosine phosphatase 2 (SHP2) is ubiquitously expressed and believed to function as part of a positive signaling pathway mediating growth factor–induced protein tyrosine phosphorylation. Proliferation of aortic vascular smooth muscle cells (SMCs) is an important contributor to atherosclerosis. We examined the effect of SHP2 expression on SMC proliferative activity. Methods and Results—SHP2 was abundant in cultured aortic SMCs, and SHP2 staining was markedly increased in the thickened aortic intima in rats with balloon-induced injury. We obtained several SMC clones by using geneticin screening. Endogenous SHP2 expression varied among individual clones. Significant positive relationships were observed between SHP2 expression and bromodeoxyuridine uptake in SMCs stimulated by FBS, platelet-derived growth factor, or insulin-like growth factor-1. In SMCs transiently transfected with SHP2, FBS stimulation significantly increased bromodeoxyuridine uptake beyond the uptake by control SMCs. Conclusions—Increased SHP2 expression in SMCs may accelerate aortic atherosclerosis by increasing cell growth.
{"title":"Role of Src Homology 2–Containing Tyrosine Phosphatase 2 on Proliferation of Rat Smooth Muscle Cells","authors":"N. Seki, N. Hashimoto, Yoshifumi Suzuki, S. Mori, K. Amano, Y. Saito","doi":"10.1161/01.ATV.0000022878.37277.EC","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022878.37277.EC","url":null,"abstract":"Objective—Src homology 2–containing phosphotyrosine phosphatase 2 (SHP2) is ubiquitously expressed and believed to function as part of a positive signaling pathway mediating growth factor–induced protein tyrosine phosphorylation. Proliferation of aortic vascular smooth muscle cells (SMCs) is an important contributor to atherosclerosis. We examined the effect of SHP2 expression on SMC proliferative activity. Methods and Results—SHP2 was abundant in cultured aortic SMCs, and SHP2 staining was markedly increased in the thickened aortic intima in rats with balloon-induced injury. We obtained several SMC clones by using geneticin screening. Endogenous SHP2 expression varied among individual clones. Significant positive relationships were observed between SHP2 expression and bromodeoxyuridine uptake in SMCs stimulated by FBS, platelet-derived growth factor, or insulin-like growth factor-1. In SMCs transiently transfected with SHP2, FBS stimulation significantly increased bromodeoxyuridine uptake beyond the uptake by control SMCs. Conclusions—Increased SHP2 expression in SMCs may accelerate aortic atherosclerosis by increasing cell growth.","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":"90533475","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.0000022849.26083.FA
K. Kornerup, B. Nordestgaard, B. Feldt-Rasmussen, K. Borch-Johnsen, K. S. Jensen, J. Jensen
Objective—The increased risk of atherosclerosis associated with diabetes cannot be explained by conventional cardiovascular risk factors alone. We hypothesized that transvascular lipoprotein transport may be increased in patients with diabetes, possibly explaining increased intimal lipoprotein accumulation and, thus, atherosclerosis. Methods and Results—We developed an in vivo method for measurement of transvascular transport of low density lipoprotein (LDL) and applied it in 16 patients with maturity-onset diabetes (type 2) and 29 healthy control subjects. Autologous 131I-labeled LDL was reinjected intravenously in addition to 125I-labeled albumin, and the 1-hour fractional escape rates were taken as indices of transvascular transport. Both parameters were normally distributed, and they were tightly correlated (R2=0.69, P <0.0001). Transvascular LDL transport was 5.4±2.9%/h and 4.1±1.5%/h in patients with diabetes and control subjects, respectively (P <0.05); equivalent values for albumin were 6.5±2.5%/h and 5.3±1.6%/h (P <0.05). This difference most likely was not caused by altered hepatic LDL receptor expression, glycosylation of LDL, small LDL size, nephropathy, statin use, or different plasma insulin levels in diabetic patients. Conclusions—Transvascular LDL transport may be increased in patients with type 2 diabetes. This suggests that lipoprotein flux into the arterial wall is increased in people with diabetes, possibly explaining the accelerated development of atherosclerosis.
目的:动脉粥样硬化与糖尿病相关的风险增加不能仅仅用传统的心血管危险因素来解释。我们假设糖尿病患者的血管内脂蛋白转运可能增加，这可能解释了内膜脂蛋白积累增加，从而导致动脉粥样硬化。方法与结果:我们建立了一种体内低密度脂蛋白(LDL)经血管转运的测定方法，并将其应用于16例成熟型糖尿病(2型)患者和29例健康对照。除125i标记的白蛋白外，再静脉注射自体131i标记的LDL，以1小时分数逃逸率作为经血管运输的指标。两个参数均为正态分布，且密切相关(R2=0.69, P <0.0001)。糖尿病患者LDL经血管转运率为5.4±2.9%/h，对照组为4.1±1.5%/h (P <0.05);白蛋白的等效值分别为6.5±2.5%/h和5.3±1.6%/h (P <0.05)。这种差异很可能不是由肝脏LDL受体表达改变、LDL糖基化、LDL小尺寸、肾病、他汀类药物使用或糖尿病患者血浆胰岛素水平不同引起的。结论:2型糖尿病患者LDL经血管转运可能增加。这表明糖尿病患者进入动脉壁的脂蛋白通量增加，这可能解释了动脉粥样硬化加速发展的原因。
{"title":"Transvascular Low-Density Lipoprotein Transport in Patients With Diabetes Mellitus (Type 2): A Noninvasive In Vivo Isotope Technique","authors":"K. Kornerup, B. Nordestgaard, B. Feldt-Rasmussen, K. Borch-Johnsen, K. S. Jensen, J. Jensen","doi":"10.1161/01.ATV.0000022849.26083.FA","DOIUrl":"https://doi.org/10.1161/01.ATV.0000022849.26083.FA","url":null,"abstract":"Objective—The increased risk of atherosclerosis associated with diabetes cannot be explained by conventional cardiovascular risk factors alone. We hypothesized that transvascular lipoprotein transport may be increased in patients with diabetes, possibly explaining increased intimal lipoprotein accumulation and, thus, atherosclerosis. Methods and Results—We developed an in vivo method for measurement of transvascular transport of low density lipoprotein (LDL) and applied it in 16 patients with maturity-onset diabetes (type 2) and 29 healthy control subjects. Autologous 131I-labeled LDL was reinjected intravenously in addition to 125I-labeled albumin, and the 1-hour fractional escape rates were taken as indices of transvascular transport. Both parameters were normally distributed, and they were tightly correlated (R2=0.69, P <0.0001). Transvascular LDL transport was 5.4±2.9%/h and 4.1±1.5%/h in patients with diabetes and control subjects, respectively (P <0.05); equivalent values for albumin were 6.5±2.5%/h and 5.3±1.6%/h (P <0.05). This difference most likely was not caused by altered hepatic LDL receptor expression, glycosylation of LDL, small LDL size, nephropathy, statin use, or different plasma insulin levels in diabetic patients. Conclusions—Transvascular LDL transport may be increased in patients with type 2 diabetes. This suggests that lipoprotein flux into the arterial wall is increased in people with diabetes, possibly explaining the accelerated development 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":"89926673","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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