Aqueous or lipid components of atherosclerotic lesion increase macrophage oxidation and lipid accumulation.
OBJECTIVE
Understanding the interactions among atherosclerotic plaque components and arterial macrophages, is essential for elucidating the mechanisms involved in the development of atherosclerosis. We assessed the effects of lesion extracts on macrophages.


METHODS
Mouse peritoneal macrophages from atherosclerotic normoglycemic or hyperglycemic apoE(-/-) mice were incubated with aortic aqueous or with aortic lipidic extracts (mAAE or mALE) derived from these mice. In parallel, J774A.1 cultured macrophages were incubated with increasing concentrations of extracts prepared from human carotid lesions: polar lesion aqueous extract (hLAE), nonpolar lesion lipid extract (hLLE), or with their combination. In all the above systems we performed analyses of macrophage oxidative status, cholesterol, and triglyceride metabolism.


RESULTS
Aqueous or lipid extracts from either mice aorta or from human carotid lesions significantly increased macrophage oxidative stress as determined by reactive oxygen species (ROS) analysis. In parallel, a compensatory increase in the cellular antioxidant paraoxonase2 (PON2) activity and in macrophage glutathione content were observed following incubation with all extracts. Macrophage triglyceride mass and triglyceride biosynthesis rate were both significantly increased following treatment with the lipid extracts, secondary to upregulation of DGAT1. All extracts decreased cholesterol biosynthesis rate, through downregulation of HMGCR, the rate limiting enzyme in cholesterol biosynthesis. The combination of the human lesion extracts had the most significant effects.


CONCLUSIONS
The present study demonstrates that atherosclerotic plaque constituents enhance macrophage cellular oxidative stress, and accumulation of cholesterol and triglycerides, as shown in both in vivo and in vitro model systems.
The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Niroz
N
Abu-Saleh
The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address: aviram@tx.technion.ac.il.
Michael
M
Aviram
The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel; Department of Internal Medicine E, Rambam Health Care Campus, Haifa, Israel.
Tony
T
Hayek
D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D050356:Lipid Metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress
ApoE(−/−) mice; Atherosclerotic lesion; Cholesterol metabolism; DGAT1; Glucose; HMGCR; Macrophages; Mouse peritoneal macrophages (MPM); Oxidative stress; Paraoxonase2; Triglyceride metabolism