Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis.

Abstract

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) betaII is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKCbeta in regulating key events linked to atherosclerosis and show that the aortas of apoE(-/-) mice display an age-dependent increase in PKCbetaII antigen in membranous fractions vs. C57BL/6 animals with a approximately 2-fold increase at age 6 wk and a approximately 4.5-fold increase at age 24 wk. Consistent with important roles for PKCbeta in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKCbeta(-/-)/apoE(-/-) vs. apoE(-/-) mice by approximately 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 approximately 2-fold was observed in apoE(-/-) mice fed ruboxistaurin chow (PKCbeta inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKCbeta-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKCbeta may be beneficial in mitigating endothelial perturbation and atherosclerosis.

• Authors: Evis Harja, Jong Sun Chang, Yan Lu, Michael Leitges, Yu Shan Zou, Ann Marie Schmidt, Shi-Fang Yan
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 23 Issue 4 Pg. 1081-91 (Apr 2009) ISSN: 1530-6860 [Electronic] United States
• PMID: 19036858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Indoles
• Maleimides
• ruboxistaurin
• Protein Kinase C
• Protein Kinase C beta
• Matrix Metalloproteinase 2

Topics

• Animals
• Aorta (metabolism, pathology)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (metabolism, pathology)
• Crosses, Genetic
• Early Growth Response Protein 1 (genetics, metabolism)
• Enzyme Activation
• Gene Expression Regulation, Enzymologic
• Homozygote
• Indoles (pharmacology)
• Male
• Maleimides (pharmacology)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Protein Kinase C (antagonists & inhibitors, deficiency, genetics, metabolism)
• Protein Kinase C beta