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...

Oxidized low-density lipoproteins play important roles in the development of atherosclerosis and contain several lipid-derived, bioactive molecules which are believed to contribute to atherogenesis. Of these, some cholesterol oxidation products, referred to as oxysterols, are suspected to favor the formation of atherosclerotic plaques involving cytotoxic, pro-oxidant and pro-inflammatory processes. Ten commonly occurring oxysterols (7alpha-, 7beta-hydroxycholesterol, 7-ketocholesterol, 19-hydroxycholesterol, cholesterol-5alpha,6alpha-epoxide, cholesterol-5beta,6beta-epoxide, 22R-, 22S-, 25-, and 27-hydroxycholesterol) were studied for both their cytotoxicity and their ability to induce superoxide anion production (O2*-) and IL-8 secretion in U937 human promonocytic leukemia cells. Cytotoxic effects (phosphatidylserine externalization, loss of mitochondrial potential, increased permeability to propidium iodide, and occurrence of cells with swollen, fragmented and/or condensed nuclei) were only identified with 7beta-hydroxycholesterol, 7-ketocholesterol and cholesterol-5beta,6beta-epoxide, which also induce lysosomal destabilization associated or not associated with the formation of monodansylcadaverine-positive cytoplasmic structures. No relationship between oxysterol-induced cytotoxicity and HMG-CoA reductase activity was found. In addition, the highest O2*- overproduction quantified with hydroethidine was identified with 7beta-hydroxycholesterol, 7-ketocholesterol and cholesterol-5beta,6beta-epoxide, with cholesterol-5alpha, 6alpha-epoxide and 25-hydroxycholesterol. The highest capacity to simultaneously stimulate IL-8 secretion (quantified by ELISA and by using a multiplexed, particle-based flow cytometric assay) and enhance IL-8 mRNA levels (determined by RT-PCR) was observed with 7beta-hydroxycholesterol and 25-hydroxycholesterol. None of the effects observed for the oxysterols were detected for cholesterol. Therefore, oxysterols may have cytotoxic, oxidative, and/or inflammatory effects, or none whatsoever.

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ObjectiveTo generate a global reference for caesarean section (CS) rates at health facilities.DesignCross‐sectional study.SettingHealth facilities from 43 countries.Population/SampleThirty eight thousand three hundred and twenty‐four women giving birth from 22 countries for model building and 10 045 875 women giving birth from 43 countries for model testing.MethodsWe hypothesised that mathematical models could determine the relationship between clinical‐obstetric characteristics and CS. These models generated probabilities of CS that could be compared with the observed CS rates. We devised a three‐step approach to generate the global benchmark of CS rates at health facilities: creation of a multi‐country reference population, building mathematical models, and testing these models.Main outcome measuresArea under the ROC curves, diagnostic odds ratio, expected CS rate, observed CS rate.ResultsAccording to the different versions of the model, areas under the ROC curves suggested a good discriminatory capacity of C‐Model, with summary estimates ranging from 0.832 to 0.844. The C‐Model was able to generate expected CS rates adjusted for the case‐mix of the obstetric population. We have also prepared an e‐calculator to facilitate use of C‐Model (www.who.int/reproductivehealth/publications/maternal_perinatal_health/c-model/en/).ConclusionsThis article describes the development of a global reference for CS rates. Based on maternal characteristics, this tool was able to generate an individualised expected CS rate for health facilities or groups of health facilities. With C‐Model, obstetric teams, health system managers, health facilities, health insurance companies, and governments can produce a customised reference CS rate for assessing use (and overuse) of CS.Tweetable abstractThe C‐Model provides a customized benchmark for caesarean section rates in health facilities and systems.