Identification of Myeloid Protein Kinase C - Epsilon as a Novel Atheroprotective Gene.

Background: Atherosclerosis is a lipid mediated chronic inflammatory disease driven my macrophages (MØ). Protein Kinase C - epsilon (PKCɛ) is is a serine/threonine kinase involved in diverse cellular processes such as migration, growth, differentiation, and survival. PKCɛ is known to act in a context dependent manner within heart, however, its role in atherosclerosis is unknown. Methods: Bone marrow derived MØ from global PKCɛ KO mice were examined for impact of lipid metabolism and inflammatory factor secretion. Public geneset analysis assessed raw counts of PKCɛ to determine translational relevance. To determine the function myeloid PKCɛ on atherosclerosis a novel murine model was generated using LysM Cre technology. After its characterization, human-like hypercholesterolemia was induced to assess plaque morphology in WT mice or mice lacking myeloid PKCɛ. Results: Public geneset analysis of human atherosclerotic plaque tissue revealed that PKCɛ expression is inversely correlated with plaque size and vulnerability. Similarly, peritoneal MØ from hypercholesterolemic mice have significantly lower PKCɛ expression. As MØ play a major role in atherogenesis, we generated a mouse strain with PKCɛ selectively deleted in the myeloid lineage (mɛKO). qPCR revealed no basal differences between genotypes in the expression of lipid uptake receptors, efflux transporters, or inflammatory markers. However, upon lipid loading, mɛKO MØs retained significantly more cholesterol than WT. Human-like hypercholesterolemia was induced in WT and mɛKO mice and assessed for lesion area and plaque morphology in aortic arches and aortic roots. We found that, compared to WT, the lesion area in mɛKO mice was significantly larger, more necrotic, had larger foam cells, and thinner collagen caps. Conclusions: Loss of myeloid PKCɛ promotes atherosclerosis as determined by larger lesions, more necrosis, thinner plaque caps). Together, these data identify myeloid PKCɛ as a novel atheroprotective gene, laying the foundation for mechanistic studies on the signaling networks responsible for the phenotype. Highlights: A novel murine model in which PKCɛ is floxed (PKCɛ