title: DPP-4 inhibitors repress foam cell formation by inhibiting scavenger receptors through protein kinase C pathway.
abstract: Studies show that dipeptidyl peptidase-4 (DPP-4) inhibitors may have an anti-atherosclerotic effect. Since foam cells are key components of atherosclerotic plaque, we studied the effect of DPP-4 inhibitors on foam cell formation. Foam cell formation was studied by treatment of THP-1 macrophages with oxidized low-density lipoprotein in the absence or presence of DPP-4 inhibitors (sitagliptin and NVPDPP728). The expression of scavenger receptors SRA, CD36 and LOX-1 was measured, and their role in foam cell formation in the presence of DPP-4 inhibitors was examined. In additional studies, role of protein kinase C and A in the effect of DPP-4 inhibitors was examined. Foam cell formation was markedly reduced by both DPP-4 inhibitors, as was the expression of CD36 and LOX-1 (CD36 ≫ LOX-1), but not SRA. Simultaneously, there was a reduction in phosphorylated PKC, but not PKA, content. Recovery of phosphorylated PKC following treatment of cells negated the effect of DPP-4 inhibitors on foam cell formation. Further, overexpression of CD36 or LOX-1 blocked the effect of DPP-4 inhibitors on foam cell formation. DPP-4 inhibitors repress foam cell formation through the inhibition of SRs CD36 and LOX-1, most likely via the inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of atherosclerosis by DPP-4 inhibitors.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Dai
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008077:Lipoproteins, LDL; D011719:Pyrazines; D051116:Receptors, Scavenger; D014230:Triazoles; C099252:oxidized low density lipoprotein; D011493:Protein Kinase C; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate