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

Autor: Michael J. Thomas, Rachel Kallinger, Mary G. Sorci-Thomas, Hao Xu, Brian Fulp, Yi Sherry Zhang, Theresa Bluemn, Ranjuna Weerasekera, Roland James, Manal Zabalawi, Kristina L. Brzoza-Lewis, Sushma Kaul, Elisa Maruko, Mark Gerelus
Rok vydání: 2016
Předmět:
0301 basic medicine
chronic inflammation
Apolipoprotein B
030204 cardiovascular system & hematology
Cytokine Receptor Common beta Subunit
chemistry.chemical_compound
Mice
0302 clinical medicine
High-density lipoprotein
Homeostasis
Coronary Heart Disease
Lipid raft
Aorta
Original Research
Mice
Knockout
lipid rafts
biology
Lipids and Cholesterol
3. Good health
Lipoproteins
LDL
microdomains
lipids (amino acids
peptides
and proteins)
Cholesterol Esters
medicine.symptom
Cardiology and Cardiovascular Medicine
medicine.medical_specialty
apolipoprotein A‐I
Blotting
Western
apolipoprotein
Inflammation
03 medical and health sciences
Membrane Microdomains
Vascular Biology
Internal medicine
medicine
Animals
Humans
Apolipoprotein A-I
Cholesterol
business.industry
Lipid microdomain
cholesterol
Atherosclerosis
signaling pathways
030104 developmental biology
Endocrinology
chemistry
Microscopy
Fluorescence
Receptors
LDL
Diet
Western
inflammation
Immunology
LDL receptor
biology.protein
Leukocytes
Mononuclear
high‐density lipoprotein
business
Cell Signalling/Signal Transduction
Basic Science Research
Lipoprotein
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: 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 CD 131 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 CD 131, 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.
Databáze: OpenAIRE
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