PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E-deficient mice.

Genomewide association studies have shown that a nonsynonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis-related complications. We examined the role of PKCη in lipid metabolism and atherosclerosis using apolipoprotein E-deficient (Apoe(-/-) ) mice. PKCη expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2-positive macrophages within atherosclerotic lesions. Prkch(+/+) Apoe(-/-) and Prkch(-/-) Apoe(-/-) mice were fed a high-fat diet (HFD), and the dyslipidemia observed in Prkch(+/+) Apoe(-/-) mice was improved in Prkch(-/-) Apoe(-/-) mice, with a particular reduction in serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch(+/+) Apoe(-/-) mice, was improved in Prkch(-/-) Apoe(-/-) mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD-fed Prkch(-/-) Apoe(-/-) mice. Immunoreactivity against 3-nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch(-/-) Apoe(-/-) mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch(-/-) Apoe(-/-) macrophages. These data show that PKCη deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe(-/-) mice, showing that PKCη plays a role in atherosclerosis development.