Work

Imatinib Promotes Reverse Cholesterol Transport and Elevates Scavenger Receptor B1

Year: 2022

Type: article

Abstract: Background: Mitogen-activated protein kinases, including JNK, ERK, and p38 mitogen-activated protein kinase, are critical in regulating the expression of various proinflammatory and anti-inflammatory cytokines and chemokines.Previous work has suggested that the absence of MAP kinase phosphatase-5 (MKP-5) inhibits oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation without influencing the MAKP activation.The current study is to determine the role of macrophage MKP-5 in the pathogenesis of atherosclerosis and underlying mechanisms.Methods: Nine-week-old male congenic MKP-5 deficient (MKP-5 e/e ) and C57Bl/6J control (WT) mice on an low-density lipoprotein (LDL) receptor knock-out (LDLR e/e ) background were fed with a high-fat diet containing 1.25% cholesterol for 14 weeks.Global deficiency of MKP-5 attenuated atherosclerotic plaque formation without altering the lipid profile in vivo.To further elucidate the macrophage-specific effect of MKP-5 in atherogenesis, lethally irradiated LDLR e/e mice were transplanted with wild-type or MKP-5 e/e bone marrow and subjected to high-fat feeding.Results: Mice transplanted with MKP-5 e/e bone marrow developed smaller atherosclerotic lesions accompanied by decreased lipid deposition and macrophage content compared with wild type.Lack of MKP-5 in macrophages reduced plasma levels of interleukin-1a (IL-1a) and IL-7, elevated anti-inflammatory cytokines IL-1 receptor antagonist (IL-1rn), and IL-4.Mechanistically, lack of MKP-5 in macrophages inhibited ox-LDL-induced foam cell formation through enhanced cholesterol efflux mediated by increased expression of ATP-binding cassette transporters ABCA1 and ABCG1.Conclusions: These data suggest that the myeloid MKP-5 deficiency reduces atherosclerosis progression and foam cell formation by ameliorating cholesterol efflux and inhibiting inflammation.

Source: JVS Vascular Science

DOI: 10.1016/j.jvssci.2022.05.050