Obesity is independently associated with increased cardiovascular risk. However, since established obesity clusters with various cardiovascular risk factors, configuring the metabolic syndrome, the early effects of obesity on vascular function are still poorly understood. The current study was designed to evaluate the effect of early obesity on coronary endothelial function in a new animal model of swine obesity. As to method, juvenile domestic crossbred pigs were randomized to either high-fat/high-calorie diet (HF) or normal chow diet for 12 wk. Coronary microvascular permeability and abdominal wall fat were determined by using electron beam computerized tomography. Epicardial endothelial function and oxidative stress were measured in vitro. Systemic oxidative stress, renin-angiotensin activity, leptin levels, and parameters of insulin sensitivity were evaluated. As a result, HF pigs were characterized by abdominal obesity, hypertension, and elevated plasma lysophosphatidylcholine and leptin in the presence of increased insulin sensitivity. Coronary endothelium-dependent vasorelaxation was reduced in HF pigs and myocardial microvascular permeability increased compared with those values in normal pigs. Systemic redox status in HF pigs was similar to that in normal pigs, whereas the coronary endothelium demonstrated higher content of superoxide anions, nitrotyrosine, and NADPH-oxidase subunits, indicating increased tissue oxidative stress. In conclusion, the current study shows that early obesity is characterized by increased vascular oxidative stress and endothelial dysfunction in association with increased levels of leptin and before the development of insulin resistance and systemic oxidative stress. Vascular dysfunction is therefore an early manifestation of obesity and might contribute to the increased cardiovascular risk, independently of insulin resistance.

Background and Purpose-Circulating lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) has emerged as a novel biomarker for cardiovascular diseases. However, the correlation between the plaque expression of Lp-PLA 2 and plaque oxidative stress, inflammation, and stability as well as the clinical presentation remains poorly defined, especially for cerebrovascular disease. Therefore, this study was performed to test the hypothesis that Lp-PLA 2 expression is higher in symptomatic than in asymptomatic carotid plaques of patients undergoing carotid endarterectomy. Methods-The expression of Lp-PLA 2 in 167 carotid artery plaques was determined by immunoblotting and immunostaining. Plaque oxidative stress, inflammation, and stability were quantified by NAD(P)H oxidase p67phox and MMP-2 immunoblotting, oxidized LDL (oxLDL) immunoreactivity, macrophage and Sirius red collagen staining. Lysophosphatidylcholine 16:0 (lysoPC) concentration was measured in 55 plaques using liquid chromatography tandem mass spectrometry. Results-Lp-PLA 2 expression was significantly higher in plaques of symptomatic patients than asymptomatic patients (1.66Ϯ0.19 versus 1.14Ϯ0.10, PϽ0.05) and localized mainly to shoulder and necrotic lipid core areas in colocalization with oxLDL and macrophage content. Similarly, Lp-PLA 2 expression was related to collagen content, which was lower in plaques from symptomatic patients than in plaques from asymptomatic patients (9.1Ϯ2.2 versus 18.5Ϯ1.7% of staining/field, PϽ0.001). LysoPC plaque concentration was significantly higher in plaques of symptomatic than asymptomatic patients (437.0Ϯ57.91 versus 228.84Ϯ37.00 mmol/L, PϽ0.05). Conclusions-Symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA 2 and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. These findings strongly support a role for Lp-PLA2 in the pathophysiology and clinical presentation of cerebrovascular disease.

Objective-The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation. Key Words: atherosclerosis Ⅲ carotid plaque Ⅲ endarterectomy Ⅲ oxidative stress Ⅲ proteasome Ⅲ stroke Ⅲ ubiquitin T he ubiquitin-proteasome system (UPS) is responsible for the nonlysosomal degradation of the majority of intracellular proteins, 1,2 thus playing a crucial role in the regulation of many cellular processes. 3 The process of ubiquitination requires various enzymatic activities, involving specific proteins, ie, E1, E2, E3, which activate and transfer polyubiquitin chains to target proteins, leading eventually to the formation of a complex which is recognized and degraded by the 26S proteasome complex. 4 This complex is composed of a 20S core particle that embodies the catalytic activity and 2 19S regulatory particles. The targets of the UPS include key regulators of cell cycle and apoptosis and various transcription factors, whose intracellular levels are finely tuned in the maintenance of the optimum equilibrium for cell division, growth, differentiation, signal transduction, and response to stress. 3,5 Many of these processes are crucially involved in the onset, progression, and complication of atherosclerosis. In particular the UPS plays a key role in the activation of NF-B, 6 which has been associated with coronary 7 and carotid 8 plaque instability. Moreover, the UPS degrades many molecules and regulators of apoptosis and angiogenesis, 3 crucial mechanisms of plaque formation and rupture. 9,10 It is therefore conceivable that dysregulation of the UPS plays a role in atherosclerotic plaque progression and tendency to rupture. Indeed, increased expression of ubiquitin conjugates has been demonstrated in human coronary plaque responsible for lethal myocardial infarction as compared with noninfarct related coronary lesions. 11 See coverA high rate of protein ubiquitination is associated with increased oxidative stress 12 especially in neurological disorders [13][14][15] and UPS has been demonstrated to be the principal system responsible for the degradation of oxidized proteins. 16 However, high-level oxidative stress can also impair UPS by reducing proteasome activity. 15,17 This could lead to intracellular accumulation of ubiquitinated substrates caused by an increased production and by a reduced degradation. As shown in the development of cataract, 18 intracellular ubiquitinated damaged proteins may eventually accumulate, form aggre-

Patch angioplasty with polyester urethane significantly reduced the restenosis rate ( P = . 01) compared with primary closure. Even though clamping time was longer, patching was not associated with more perioperative complications.

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