GLP-1 agonists inhibit ox-LDL uptake in macrophages by activating protein kinase A.
Oxidized low-density lipoprotein (ox-LDL) uptake by monocytes/macrophages plays a pivotal role in atherogenesis. This study was designed to examine the effect of glucagon-like peptide-1 (GLP-1) agonists on ox-LDL uptake in macrophages. Human primary monocytes/macrophages were incubated with native GLP-1 (nGLP-1) or GLP-1 agonist liraglutide to evaluate their effect on ox-LDL uptake and the expression of scavenger receptors (SRs), such as SR-A, CD36, and lectin-like ox-LDL SR-1, in this process. Our study showed a decrease in ox-LDL uptake and CD36 expression in macrophages treated with nGLP-1 or liraglutide. However, nGLP-1 and liraglutide did not affect the expression of other SRs SR-A and lectin-like ox-LDL SR-1. Simultaneously, there was an increase in the expression of activated protein kinase A (PKA). To examine the role of PKA in the effects of nGLP-1 or liraglutide, we treated macrophages with PK inhibitor (6-22) amide, a PKA inhibitor, followed by treatment with nGLP-1 or liraglutide. Inhibition of PKA activation markedly reversed the effect of nGLP-1 or liraglutide on ox-LDL uptake and enhanced the expression of CD36. Our results suggest that GLP-1 agonism inhibits ox-LDL uptake through PKA/CD36 pathway in macrophages. This study provides a novel insight in the mechanism of foam cell formation and the role by GLP-1 agonists therein.
*Division of Cardiology, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR; Departments of †Endocrinology; and ‡Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China; and §Department of Geriatric Endocrinology, Chinese PLA General Hospital, Beijing, China.
Yao
Y
Dai
Dongsheng
D
Dai
Xianwei
X
Wang
Zufeng
Z
Ding
Chunlin
C
Li
Jawahar L
JL
Mehta
D050197:Atherosclerosis / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D000069450:Liraglutide; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases