Lipid-Free Apolipoprotein A-I Reduces Progression of Atherosclerosis by Mobilizing Microdomain Cholesterol and Attenuating the Number of CD131 Expressing Cells: Monitoring Cholesterol Homeostasis Using the Cellular Ester to Total Cholesterol Ratio. J Am Heart Assoc 2016 Nov 07;5(11)
Date
11/09/2016Pubmed ID
27821400Pubmed Central ID
PMC5210328DOI
10.1161/JAHA.116.004401Scopus ID
2-s2.0-85032586305 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
BACKGROUND: Atherosclerosis is a chronic inflammatory disorder whose development is inversely correlated with high-density lipoprotein concentration. Current therapies involve pharmaceuticals that significantly elevate plasma high-density lipoprotein cholesterol concentrations. Our studies were conducted to investigate the effects of low-dose lipid-free apolipoprotein A-I (apoA-I) on chronic inflammation. The aims of these studies were to determine how subcutaneously injected lipid-free apoA-I reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without sustained elevations in plasma high-density lipoprotein cholesterol concentrations.
METHODS AND RESULTS: Ldlr-/- and Ldlr-/- apoA-I-/- mice were fed a Western diet for a total of 12 weeks. After 6 weeks, a subset of mice from each group received subcutaneous injections of 200 μg of lipid-free human apoA-I 3 times a week, while the other subset received 200 μg of albumin, as a control. Mice treated with lipid-free apoA-I showed a decrease in cholesterol deposition and immune cell retention in the aortic root compared with albumin-treated mice, regardless of genotype. This reduction in atherosclerosis appeared to be directly related to a decrease in the number of CD131 expressing cells and the esterified cholesterol to total cholesterol content in several immune cell compartments. In addition, apoA-I treatment altered microdomain cholesterol composition that shifted CD131, the common β subunit of the interleukin 3 receptor, from lipid raft to nonraft fractions of the plasma membrane.
CONCLUSIONS: ApoA-I treatment reduced lipid and immune cell accumulation within the aortic root by systemically reducing microdomain cholesterol content in immune cells. These data suggest that lipid-free apoA-I mediates beneficial effects through attenuation of immune cell lipid raft cholesterol content, which affects numerous types of signal transduction pathways that rely on microdomain integrity for assembly and activation.
Author List
Kaul S, Xu H, Zabalawi M, Maruko E, Fulp BE, Bluemn T, Brzoza-Lewis KL, Gerelus M, Weerasekera R, Kallinger R, James R, Zhang YS, Thomas MJ, Sorci-Thomas MGAuthors
Theresa Bluemn Research Scientist I in the Pediatrics department at Medical College of WisconsinMary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAorta
Apolipoprotein A-I
Atherosclerosis
Blotting, Western
Cholesterol
Cholesterol Esters
Cytokine Receptor Common beta Subunit
Diet, Western
Homeostasis
Humans
Leukocytes, Mononuclear
Lipoproteins, LDL
Membrane Microdomains
Mice
Mice, Knockout
Microscopy, Fluorescence
Receptors, LDL
