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) βII is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKCβ in regulating key events linked to atherosclerosis and show that the aortas of apoE −/− mice display an age-dependent increase in PKCβII antigen in membranous fractions vs. C57BL/6 animals with a ∼2-fold increase at age 6 wk and a ∼4.5-fold increase at age 24 wk. Consistent with important roles for PKCβ in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKCβ −/− /apoE −/− vs. apoE −/− mice by ∼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 ∼2-fold was observed in apoE −/− mice fed ruboxistaurin chow (PKCβ inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKCβ-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKCβ 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 PKCβ and apolipoprotein E display decreased atherosclerosis.
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Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis
Harja, Evis; Chang, Jong Sun; Lu, Yan; Leitges, Michael; Zou, Yu Shan; Schmidt, Ann Marie; Yan, Shi-Fang
Follow The FASEB Journal
, Volume 23 (4): 1081
Fed of American Socs for Experimental Biology – Apr 1, 2009
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