Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid Induced PKCδ Isoform Activation
Rationale: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes and obesity contributes to the development of atherosclerosis. PKCδ expression and activity in monocytes were increased by hyperlipidemia and diabetes with unknown consequences to atherosclerosis.
Objective: To investigate the effect of PKCδ activation in macrophages on the severity of atherosclerosis.
Methods and Results: PKCδ expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCδ in macrophages were generated by breeding PKCδ flox/flox mice with LyzM-Cre and ApoE-/- mice (MPKCδKO/ApoE-/- mice) and studied in atherogenic (AD) and very high fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD fed mice had insulin resistance and mild diabetes. Surprisingly, MPKCδKO/ApoE-/- mice exhibited accelerated aortic atherosclerotic lesions by 2-fold vs. ApoE-/- mice on AD or HFD. Splenomegaly was observed in MPKCδKO/ApoE-/- mice on AD and HFD, but not on regular chow. Both the AD or HFD increased macrophage numbers in aortic plaques and spleen by 1.7 and 2-fold, respectively, in MPKCδKO/ApoE-/- vs. ApoE--/- mice due to decreased apoptosis (62%) and increased proliferation (1.9 fold), and not due to uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE-/- were associated with elevated phosphorylation levels of pro-survival cell signaling proteins, Akt and FoxO3a, with reduction of pro-apoptotic protein Bim associated with PKCδ induced inhibition of P85/PI3K.
Conclusions: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCδ isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.
- Received June 27, 2017.
- Revision received August 23, 2017.
- Accepted August 29, 2017.