ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The production of collagen is fundamental to atherosclerosis and critically dependent on posttranslational modification by prolyl 4-hydroxylase.Methods and Results—We report the cloning of a novel prolyl 4-hydroxylase catalytic (&agr;) subunit from human vascular smooth muscle cells. The peptide displayed conservation of critical residues for interacting with Fe2+and 2-oxoglutarate, essential cosubstrates for prolyl 4-hydroxylase activity. Furthermore, when the recombinant protein was expressed in cells, it associated with the &bgr;-subunit of prolyl 4-hydroxylase and could catalyze prolyl 4-hydroxylation of a collagen-like peptide. The tissue distribution was dissimilar from that of the 2 previously cloned &agr;-subunits, suggesting a role beyond redundancy. Importantly, the novel gene was expressed in the fibrous cap of human carotid atherosclerotic lesions.Conclusions—The discovery of a novel prolyl 4-hydroxylase &agr;-subunit, here termed the &agr;(III)-subunit, suggests a new participant in collagen synthesis that, in view of the expression findings, may be relevant to atherosclerotic disease.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—C-reactive protein (CRP), an acute-phase reactant long considered merely an innocent bystander in the inflammatory process, is now recognized as a powerful predictor of cardiovascular events. Emerging in vitro evidence suggests that CRP may have direct proinflammatory and prothrombotic effects on monocytes and endothelial cells. To determine whether CRP directly modulates vascular cell function in vivo, we subjected wild-type mice, which do not express CRP, and human CRP–transgenic (CRPtg) mice to 2 models of arterial injury.Methods and Results—Baseline serum CRP levels in CRPtg mice were 18±6 mg/L. CRP levels were undetectable in wild-type mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 75% of CRPtg arteries (6 of 8) compared with 17% (2 of 12) in wild-type mice (P<0.05). In a model of arterial photochemical injury, clot formation time was shortened in CRPtg mice; mean time to occlusion was 33±19 minutes compared with 59±19 minutes in wild-type mice (n=10;P<0.05).Conclusions—Arterial injury in CRPtg mice results in an expedited and higher rate of thrombotic occlusion. This is the first report of a prothrombotic phenotype directly attributable to the presence of human CRP in vivo. Investigation of the inflammatory-thrombotic axis in CRPtg mice may elucidate the prothrombotic actions of CRP in unstable arterial diseases and may pave the way for novel therapeutic interventions for preventing cardiovascular events.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood.Methods and Results—Using IL-1Ra–deficient (IL-1Ra−/−; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra−/−mice increased by 249% (31.8±2.9 &mgr;m [n=10] versus 9.1±0.7 &mgr;m [n=10];P<0.0001) and 257% (2.5±0.2 versus 0.7±0.1;P<0.0001), respectively, compared with IL-1Ra+/+mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1&bgr; and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra+/+but not IL-1Ra−/−mice.Conclusions—The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Conventional wisdom suggests that a diagnosis of familial combined hyperlipidemia (FCHL) carries a substantially greater risk of premature coronary artery disease (CAD) than a diagnosis of familial hypertriglyceridemia (FHTG). However, no population-based studies have critically addressed this issue.Methods and Results—FCHL and FHTG were diagnosed in 10.2% and 12.3% of 334 random control families and in 16.7% and 20.5% of 293 families with at least one case of premature CAD. The diagnosis of either FCHL or FHTG in an individual was associated with an odds ratio for CAD of 2.0 (P=0.003 and 0.002, respectively). However, odds ratios for premature CAD associated with both lipid disorders decreased substantially and identically with further adjustment for hypertension, diabetes, and especially HDL cholesterol, triglycerides, or apolipoprotein B. Similar results were found for differences in carotid intima-medial thickness and ankle-brachial index. Metabolic syndrome was identified in 65% of FCHL and 71% of FHTG patients compared with 19% in controls without FCHL or FHTG and was associated with an odds ratio of 3.3 (P<0.0001). The increased prevalence of the metabolic syndrome alone could account for the elevated CAD risk associated with both FCHL and FHTG.Conclusions—FCHL and FHTG appear more alike than dissimilar. Further, the risk of CAD in FCHL and FHTG was strongly related to features of the metabolic syndrome. These findings suggest that the hypertriglyceridemia in FHTG is not benign and may warrant a change in epidemiological, genetic, and clinical approaches to these lipid disorders.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects.Methods and Results—Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index &bgr;) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index &bgr;. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectin–positive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol.Conclusions—Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans.Methods and Results—We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% &OV0312;o2max; moderate, 50% &OV0312;o2max; and high, 75% &OV0312;o2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-induced vasodilation (7.5±2.4 to 11.4±5.8 mL/min per 100 mL tissue;P<0.05). No intensity of aerobic exercise altered isosorbide dinitrate–induced vasodilation. The administration of NG-monomethyl-l-arginine, a nitric oxide synthase inhibitor, abolished the moderate-intensity exercise-induced augmentation of the forearm blood flow response to acetylcholine. High-intensity exercise increases plasma concentrations of 8-hydroxy-2′-deoxyguanosine (from 6.7±1.1 to 9.2±2.3 ng/mL;P<0.05) and serum concentrations of malondialdehyde-modified low-density lipoprotein (from 69.0±19.5 to 82.4±21.5 U/L;P<0.05), whereas moderate exercise tended to decrease both indices of oxidative stress.Conclusions—These findings suggest that moderate-intensity aerobic exercise augments endothelium-dependent vasodilation in humans through the increased production of nitric oxide and that high-intensity exercise possibly increases oxidative stress.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID