Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKC? Isoform Activation.

ABSTRACT: RATIONALE:Activation of monocytes/macrophages by hyperlipidemia associated with diabetes mellitus and obesity contributes to the development of atherosclerosis. PKC? (protein kinase C ?) expression and activity in monocytes were increased by hyperlipidemia and diabetes mellitus with unknown consequences to atherosclerosis. OBJECTIVE:To investigate the effect of PKC? activation in macrophages on the severity of atherosclerosis. METHODS AND RESULTS:PKC? expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKC? in macrophages were generated by breeding PKC? flox/flox mice with LyzM-Cre and ApoE-/- mice (MPKC?KO/ApoE-/- mice) and studied in atherogenic (AD) and high-fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin resistance and mild diabetes mellitus. Surprisingly, MPKC?KO/ApoE-/- mice exhibited accelerated aortic atherosclerotic lesions by 2-fold versus ApoE-/- mice on AD or HFD. Splenomegaly was observed in MPKC?KO/ApoE-/- mice on AD and HFD but not on regular chow. Both the AD or HFD increased macrophage number in aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKC?KO/ApoE-/- versus ApoE-/- mice because of decreased apoptosis (62%) and increased proliferation (1.9-fold), and not because of uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKC?KO/ApoE-/- were associated with elevated phosphorylation levels of prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of proapoptotic protein Bim associated with PKC? induced inhibition of P85/PI3K. CONCLUSIONS:Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKC? isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.

SUBMITTER: Li Q 

PROVIDER: S-EPMC6176491 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature