Annelise Genoux

Stimulation of Cell Surface F1-ATPase Activity by Apolipoprotein A-I Inhibits Endothelial Cell Apoptosis and Promotes Proliferation

Objectives—Several findings argue for a protective effect of high-density lipoproteins (HDLs) against endothelial dysfunction. The molecular mechanisms underlying this protective effect are not fully understood, although recent works suggest that the actions of HDL on the endothelium are initiated by multiple interactions between HDLs (lipid or protein moiety) and cell surface receptors. We previously showed that the mitochondrial related F1-ATPase is a cell surface receptor for HDLs and their main atheroprotective apolipoprotein (apoA-I). Herein we test the hypothesis that the cell surface F1-ATPase may contribute to the ability of apoA-I and HDLs to maintain endothelial cell survival. Methods and Results—Cell imaging and binding assays confirmed the presence of the F1-ATPase at the surface of human umbilical vein endothelial cells (HUVECs) and its ability to bind apoA-I. Cell surface F1-ATPase activity (ATP hydrolysis into ADP) was stimulated by apoA-I and was inhibited by its specific inhibitor IF1-H49K. Furthermore the antiapoptotic and proliferative effects of apoA-I on HUVECs were totally blocked by the F1-ATPase ligands IF1-H49K, angiostatin and anti-&bgr;F1-ATPase antibody, independently of the scavenger receptor SR-BI and ABCA1. Conclusion—This study suggests an important contribution of cell surface F1-ATPase to apoA-I–mediated endothelial cell survival, which may contribute to the atheroprotective functions of apoA-I.

Iron Status Is Associated with Carotid Atherosclerotic Plaques in Middle-Aged Adults

Although the iron-heart disease hypothesis is prevalent, the epidemiological findings are incongruent. The relationship of serum ferritin with early cardiovascular disease (CVD), particularly atherosclerosis, has not been evaluated extensively, particularly with accounting for inflammation. We examined this association in a case-control study of 124 age- and sex-matched pairs embedded in the population-based random sample (MONICA survey) in Southwest France, taking into account inflammation status. Cases had >or=2 carotid atherosclerotic plaques and controls had none. Inflammation was assessed using several markers, including serum alpha-1 acid glycoprotein (AGP) and high sensitivity C-reactive protein. There was an interaction of inflammation with group (case/control) for serum ferritin. In adults without elevated AGP, serum ferritin was significantly greater in atherosclerotic cases than in adults in the control group. In models adjusted for CVD risk factors, the odds of atherosclerosis increased with the increase in serum ferritin in individuals without elevated AGP; for every 10-microg/L increase in serum ferritin, the risk for atherosclerosis increased by 3% (odds ratio [95% CI]: 1.03 [1.01-1.06]). In conclusion, carotid atherosclerosis was positively associated with serum ferritin in individuals free from subclinical inflammation based on AGP. Further prospective and/or experimental studies are needed to corroborate the observed association of iron status with atherosclerosis.

Impact of genetic polymorphisms on the risk of lipid disorders in patients on anti-HIV therapy.

Abstract Active anti-HIV therapy can induce hypertriglyceridemia, low high-density lipoprotein (HDL) and insulin resistance, eventually accompanied by clinical lipodystrophy, associated loss of subcutaneous adipose tissue and an increase in abdominal adiposity. The frequency of these metabolic disorders is approximately 50% and host genetic factors might confer particular susceptibility. Variants of apolipoproteins (apo) A5 and C3, interacting with APOE genotypes, have been associated with the severity of antiretroviral therapy-induced dyslipidemia and with occurrence of lipodystrophy, and for APOC3, with objective criteria of fat redistribution. Genetic polymorphisms of the nuclear transcription-factor sterol response element-binding proteins (SREBP1c) and of tumor necrosis factor-α (TNFα) have yielded contrasting results. Other candidate genes will be explored to define a pharmacogenomic strategy to identify patients at high risk of metabolic disorders upon antiretroviral therapy. Clin Chem Lab Med 2007;45:815–21.

Serum inhibitory factor 1, high-density lipoprotein and cardiovascular diseases.

Purpose of review The atheroprotective properties of HDL are supported by epidemiological and preclinical research. However, the results of interventional trials paradoxically indicate that drugs increasing HDL-cholesterol (HDL-C) do not reduce coronary artery disease (CAD) risk. Moreover, Mendelian randomization studies have shown no effect of HDL-C-modifying variants on CAD outcome. Thus, the protective effects of HDL particles are more governed by their functional status than their cholesterol content. In this context, any successful clinical exploitation of HDL will depend on the identification of HDL-related biomarkers, better than HDL-C level, for assessing cardiovascular risk and monitoring responses to treatment. Recent findings Recent studies have enlightened the role of ecto-F1-ATPase as a cell surface receptor for apoA-I, the major apolipoprotein of HDL, involved in the important metabolic and vascular atheroprotective functions of HDL. In the light of these findings, the clinical relevance of ecto-F1-ATPase in humans has recently been supported by the identification of serum F1-ATPase inhibitor (IF1) as an independent determinant of HDL-C, CAD risk and cardiovascular mortality in CAD patients. Summary Serum IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in high-risk populations or to determine pharmacotherapy.

0084: Big data and LDL: heterozygous familial hypercholesterolemia is common in France

Background Heterozygous Familial Hypercholesterolemia (HeFH) is a severe autosomal dominant disease which is under-diagnosed. The prevalence of HeFH has rarely been assessed in an unselected sample from the general population. Methods Based on a huge sample of lipid panels, we assessed the prevalence of individuals classified with definite or probable HeFH (Dutch Lipid Clinic Network (DLCN) criteria)xa0>5 that is to say LDL-cholesterol (LDL-C)xa0>6.5mmol/L (251mg/dL). From 2006 to 2015, 200 620 LDL-C were obtained from 105 398 subjects in a large database of a French University Hospital. Subjects from 0 to 102 years (53.7±20.5) and of both genders were analysed. LDL-C levels were calculated with the Friedewald or the Planella formula if elevated triglycerides. We also assessed the prevalence of all DLCN LDL-C criteria: 4.0-4.9mmol/L (155-190mg/dL); 5.0-6.4mmol/L (191-250mg/dL); 6.5-8.4mmol/L (251-325mg/dL);xa0>8.5mmol/L (>325mg/dL). Results The prevalence of LDL-C between 4.0 and 4.9mmol/L was 9.81% [95% CI: 9.68-9.94]; the prevalence of LDL-C between 5.0 and 6.4mmol/L was 2.41% [95% CI: 2.35-2.48]; the prevalence of LDL-C between 6.5 and 8.4mmol/L was 0.37% [95% CI: 0.34-0.39] and the prevalence of LDL-Cxa0>8.5mmol/L was 0.09% [95% CI: 0.08-0.10]. In the first lipid determinations of 105 398 subjects, the prevalence of LDL-C between 4.0 and 4.9mmol/L was 10.77% [95% CI: 10.6-11.0]; between 5.0 and 6.4mmol/L was 2.47% [95% CI: 2.38-2.56]; between 6.5 and 8.4mmol/L was 0.28% [95% CI: 0.25-0.32] and of LDL-Cxa0>8.5mmol/L was 0.06% [95% CI: 0.04-0.07]. The prevalence of definite or probable HeFH was 0.46% in 200 620 lipid determinations and 0.34% in 105 398 subjects. The highest prevalence of definite or probable HeFH was in subjects aged between 35 and 55 years. Conclusions In France, the prevalence of definite or probable HeFH was 1/250 adults, very closed to the observed prevalence of 1/200 obtained in the Copenhagen General Population Study.

0470 : Serum IF1 concentration as a predictor of mortality in coronary heart disease patients

Aim The ecto-F1-ATPase/P2Y13 pathway plays a key role in reverse cholesterol transport. Exogenous IF1, known as the natural mitochondrial specific inhibitor of F1-ATPase activity, inhibits ecto-F1-ATPase activity and decreases HDL-C uptake by hepatocytes. We previously found that IF1 is present in human serum and is negatively associated with coronary heart disease (CHD). Here, we investigated the relationship between serum IF1 concentration and mortality in CHD patients. Methods Serum IF1 was measured in 624 CHD patients aged 45-74 from the GENES (Genetique et ENvironement en Europe du Sud) study. After 9.1 years follow up, mortality rate was 24.5%. Results Patients who had died were older at inclusion, were more often treated for dyslipidemia or diabetes mellitus, had higher tobacco consumption, CRP level but lower physical activity. Resting heart rate and the Gensini score of CHD severity were higher while LVEF (Left Ventricular Ejection Fraction) was decreased. They also had lower serum IF1 concentration (0.41 vs 0,44μg/ml, p=0.03). In CHD patients, IF1 concentration was negatively associated with triglycerides, Gensini score and resting heart rate and positively with physical activity, HDL-C and LVEF. HDL-C was correlated with the Gensini score but not with resting heart rate and LVEF. Serum IF1 in the two highest quartiles (≥0,42μg/ml) was associated with significantly reduced mortality risk, even after multivariate adjustments for classical cardiovascular risk factors and Gensini score (HR=0.55, p=0.026 for the highest quartile). Significance was lost after adjustment for LVEF (HR=0.72, p=0.23). Conclusion High serum IF1 is predictor of reduced mortality in CHD patients. This prognostic value remains significant whatever the value of HDL-C and Gensini score, a marker of atheroma diffusion, but was lost after adjustment for LVEF. Correlation between serum IF1 concentration and LVEF might underlie the relationship between IF1 level and mortality.