Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCδ Isoform Activation

Abstract

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. Conclusion: 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.

Monocyte Recruitment Versus Macrophage Proliferation in Atherosclerosis

“…A similar finding was reported by Lindau et al, who demonstrated that reduced circulating monocyte levels only affected early lesions but not more advanced atherosclerotic lesions 11 . In the present study, Li et al demonstrated that myeloid cell deficiency in PKCδ indeed increase macrophage proliferation in the atherosclerotic lesion (figure) 4 . The authors could show increases in both BrdU-incorporation and Ki67-staining in PKCδ-deficient macrophages in the atherosclerotic lesion, both which are markers of proliferation.…”

“…On the contrary, selective deletion of PKCδ in myeloid cells, using LysM-Cre-mediated deletion, dramatically increased atherosclerosis 4 . The increased atherosclerosis was associated with an increase in lesional macrophage accumulation, but with no evidence of increased recruitment of monocytes into the lesion.…”

“…In this issue of Circulation Research , Li and co-workers demonstrate an unexpected role for Protein Kinase C-δ (PKCδ) in monocytes and macrophages in the development of atherosclerosis in a mouse model 4 . PKCδ is part of a group of PKCs that are typically activated by diacylglycerol, and PKCδ is thought to play an important role in the development of insulin resistance and perhaps its complications 5 , but its role atherosclerosis is unknown.…”

“…Some studies 6 , but not all 7 , have suggested that PKCδ is involved in foam cell formation, a hallmark of atherosclerosis. Li and co-workers demonstrate that PKCδ is induced in monocytes and macrophages in response to dyslipidemia and inflammatory stimuli associated with metabolic disease and atherosclerosis, but that myeloid cell PKCδ does not appear to play any role in macrophage lipid loading in vivo 4 .…”

Multimodality Molecular Imaging of Cardiovascular Disease Based on Nanoprobes

“…Apoptosis also plays a crucial role in human cardiovascular diseases, including atherosclerosis [61,62], myocardial infarction [63], and heart failure [64]. The identification of annexin V as a high-affinity ligand to apoptotic cells presented a natural opportunity to apply molecular imaging technology in imaging apoptosis in vivo.…”