The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca 2؉ oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH 2 -terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.Atherosclerosis is a slow degenerative process and is the underlying cause of heart attacks, strokes, and peripheral artery diseases in humans. This complex disorder is characterized by a remodeling of the arterial wall, leading to the formation of an atherosclerotic plaque. Plaque formation is induced by the accumulation, at the subendothelial level, of oxidized low-density lipoproteins (LDLs) and subsequently of some of their lipid constituents (oxysterols, oxidized fatty acids, aldehydes, and lysophospholipids) and fibrous elements.To date, a number of studies have shown that oxysterols constitute an important family of oxygenated derivatives of cholesterol that exert potent biological effects in the pathogenesis of atherosclerosis (for a review, see references 6 and 9). Among the oxysterols that have been identified, those oxidized at the C7 position, such as 7-ketocholesterol (7-Kchol), are the ones most frequently detected at high levels in atherosclerotic plaques (9) and in the plasma of patients with high cardiovascular risk factors (55). 7-Kchol exerts deleterious effects on vascular smooth muscle cells (SMCs), including the stimulation of reactive oxygen species (ROS) production (28) and the induction of apoptosis (30,34,42), two major events involved in atherogenesis. The oxidation of macromolecules (proteins, lipids, and DNA) and apoptosis induce the progression of atherosclerosis. Thus, the death of vascular SMCs and monocyte-derived foam cells has been shown to modulate the cellularity of...

Reduced pulmonary function is an important predictor of cardiovascular morbidity and mortality. The mechanisms underlying this association are unknown but may involve systemic inflammation. We assessed the cross-sectional and longitudinal relationships between C-reactive protein (CRP) levels and forced expiratory volume in 1s (FEV1) and its decline in the general population, over a period of 8.5 years. The analyzes were based on 531 subjects (mean age at baseline: 37+/-7 years, 50% women and 42% non-smokers), recruited at two French centers participating in the European Community Respiratory Health Survey. Lung function was expressed as a percentage of predicted FEV1. CRP was measured centrally, by means of a highly sensitive assay. In cross-sectional analysis, FEV1 as a % of predicted values was negatively associated with serum CRP concentration (P=0.002). Multivariate adjustment did not alter these results (P=0.002). In longitudinal analysis, annual FEV1 decline tended to increase from the lower to the upper tertile for baseline CRP concentration but the association was borderline significant (P=0.14). Mean values of annual FEV1 decline were 26+/-32, 31+/-32, and 34+/-32 ml/year for the lower, middle and upper tertiles of baseline CRP concentration, respectively, after adjusting for potential confounders (P=0.09). Changes in CRP levels during follow-up were associated with annual FEV1 decline. The mean annual FEV1 declines in subjects with increasing CRP, in those with stable CRP and in those with decreasing CRP were 36+/-31, 30+/-31 and 24+/-31 ml/year, respectively (P<0.001). These findings were not affected by adjustment for potential confounders (P=0.002). In conclusion, increases in CRP levels over time were associated with a steeper FEV1 decline.

Background: C-reactive protein (CRP), a marker of systemic inflammation, is a powerful predictor of adverse cardiovascular events. Respiratory impairment is also associated with cardiovascular risk. Although some studies have found an inverse relationship between lung function and markers of systemic inflammation, only one study has reported a relationship between lung function and CRP levels. In contrast, little is known about the relationship between bronchial hyperresponsiveness (BHR) and systemic inflammation. The association between lung function and CRP and between BHR and CRP has been investigated. Methods: As part of the European Community Respiratory Health Survey follow up study serum CRP levels, forced expiratory volume in 1 second (FEV 1 ), and BHR to methacholine (>20% decrease in FEV 1 to ,4 mg methacholine) were measured in 259 adults aged 28-56 years free of cardiovascular disease or respiratory infection. Results: Mean (SD) FEV 1 (adjusted for age, sex, height, and smoking status) was lower in subjects with a high CRP level (high tertile) (3.29 (0.44) l/s v 3.50 (0.44) l/s; p,0.001) and BHR was more frequent (41.9% v 24.9%; p = 0.005) than in subjects with lower CRP levels (low+middle tertiles). Similar results were obtained when the potential confounding factors were taken into account. Similar patterns of results were found in non-smokers and in non-asthmatic subjects. Conclusions: Increased CRP levels are strongly and independently associated with respiratory impairment and more frequent BHR. These results suggest that both respiratory impairment and BHR are associated with a systemic inflammatory process.

The olive oil-based emulsion was well tolerated, maintained a normal EFA status, and may be more suitable for prevention of lipid peroxidation than the soybean-oil-based emulsion.