Dual effects of oxidized LDL on vascular cells
Anne Nègre-Salvayre1, Caroline Camaré1,2, Robert Salvayre1,2
1 INSERM UMR 1048, University of Toulouse, France
2 INSERM UMR 1048 and Biochemistry Laboratory, Faculty of Medicine Rangueil, University of Toulouse, France
The oxidative theory of atherosclerosis relies on the modification of low density lipoproteins by reactive oxygen species in the vascular wall and their involvement in foam cell accumulation and the generation of early atherosclerotic lesions (fatty streaks). The role of oxidized LDL in advanced lesions is debated, mainly because antioxidant supplementation failed to prevent coronary heart disease events and mortality in intervention randomized trials. However oxidized LDL and lipids accumulate in the necrotico-lipid core of atherosclerotic lesions, and may contribute to the development of advanced lesions and the promotion of pathological events such as plaque erosion and rupture. A characteristic feature of oxidized LDL signalling is their dual opposite effects, depending on the extent of lipid oxidation, the oxidized lipid content (oxidized phospholipids, oxysterols, malondialdehyde, α,β-unsaturated hydroxyalkenals), the uptake by scavenger receptors with different signalling properties, such as CD36, LOX-1 or the SRA system, their ability to trigger oxidative stress and inflammation. Low concentrations of mildly oxidized LDL are proinflammatory and induce smooth muscle cell migration and proliferation, whereas higher concentrations trigger cell growth arrest and are proapoptotic. Likewise, low oxidized LDL concentrations are proangiogenic, thus may contribute to the plaque neovascularization, whereas higher concentrations are not angiogenic and trigger apoptosis, that may lead to microcapillary fragilization, intraplaque microhemorragic events and lesion destabilization.The interplay between survival and apoptotic responses evoked by oxidized LDL and lipids depends on cellular systems that regulate the cell fate, such as the ceramide/sphingosine 1-phosphate rheostat, the endoplasmic reticulum stress or the autophagy/mitophagy pathway, but also systems that regulate the influx, residence time and lipid composition of LDL, the intensity of oxidative stress, the induction of defence mechanisms (antioxidant systems, heat shock proteins). As a consequence, the local cellular responses to oxidized LDL may stimulate inflammatory or anti-inflammatory pathways, angiogenic vs antiangiogenic responses, survival vs apoptotic events that should contribute to plaque stabilization or at the opposite, plaque fragilization and rupture. The complexity of these responses to oxidized LDL and lipids may in part explain the lack of antioxidant efficacy in human studies, since in the cellular response to oxidized LDL retention, the mechanism of protection and the identity of protective agents remain largely unknown and require further research.
Abbreviated CV
Team 10 Lipid peroxidation, signalling and Vascular Diseases (LIPSIV)
INSERM UMR1048 – Institute of Metabolic and Cardiovascular Diseases
CHU Rangueil, BP84221
31432 – Toulouse Cedex 4
Tel/Fax +33 561 322 059
Email: anne.negre-salvayre@inserm.fr
Dr. Anne Negre-Salvayre is Pharmacist (1976) specialized in Medical Biology (1977-1980), Pharm. D (1983) and Ph.D (1987) from the University Paul Sabatier in Toulouse. She spent several months per year as postdoctoral fellow at the Hadassah Medical School in Jerusalem, Israel from 1983 to 1988. She served as Medical Instructor in Biochemistry at the CHU Purpan (1978-1985), and assistant-professor in Physiology at the Faculty of Medicine Rangueil (1982-1983) in Toulouse. She is Researcher Scientist at CNRS since 1985.
She is presently Senior Researcher (DR1-CNRS), Head of the Team Lipid Peroxidation Signalling and Vascular Diseases at INSERM UMR1048 in Toulouse. She is Deputy Director of INSERM UMR1048 since January 2016.
Dr. Negre-Salvayre is author or co-author of more than 200 PubMed-indexed publications and national or international communications. She is Associate Editor for the British Journal of Pharmacology, expert or external referee for international academic and non-academic councils including INSERM, HCERES, or the Medical Research Council, member of The New French Society for Atherosclerosis, the Society for Free Radical Research and the 4-HNE-Club.
Dr. Negre-Salvayre is expert in the field of lipid and sphingolipid biochemistry, lipid peroxidation and the role of oxidative stress in the pathophysiology of atherosclerosis.
