Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis

Endothelial activation is a central initiating event in atheroma formation. Evidence from our laboratory and others has demonstrated links between activation of early growth response-1 (Egr-1) and atherosclerosis and also has demonstrated that activated protein kinase C (PKC) beta II is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKC beta in regulating key events linked to atherosclerosis and show that the aortas of apoE(-/-) mice display an age-dependent increase in PKC beta II antigen in membranous fractions vs. C57BL/6 animals with a similar to 2-fold increase at age 6 wk and a similar to 4.5-fold increase at age 24 wk. Consistent with important roles for PKC beta in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKC beta(-/-)/apoE(-/-) vs. apoE(-/-) mice by similar to 5-fold, in parallel with significantly reduced vascular transcripts for Egr-1 and matrix metalloproteinase (MMP)-2 antigen and activity vs. apoE(-/-) mice. Significant reduction in atherosclerosis of similar to 2-fold was observed in apoE(-/-) mice fed ruboxistaurin chow (PKC beta inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKC beta-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKC beta may be beneficial in mitigating endothelial perturbation and atherosclerosis.-Harja, E., Chang, J. S., Lu, Y., Leitges, M., Zou, Y. S., Schmidt, A. M., Yan, S.-F. Mice deficient in PKC beta and apolipoprotein E display decreased atherosclerosis. FASEB J. 23, 1081-1091 (2009)