The immediate early gene, early growth response-1 (egr-1), is linked to maladaptive host response mechanisms m settings of acute cellular perturbation. In addition to acute stress, up regulation of egr-1 may be linked to chronic vascular stress. Transcripts for egr-1 were up regulated in both human and murine atherosclerotic lesions compared to adjacent non-atheromatous plaque, thereby suggesting that the impact of egr-1 in vascular stress might not be limited to the acute setting, rather that egr-1 might impact on chronic vascular perturbation, such as atherosclerosis. Our preliminary studies support this concept, as real time PCR revealed a time-dependent .increase in egr-1 transcripts in aortae of apo E (0) mice versus C57BL/6 controls at ages 6, 8, 10, 14 &24 weeks. Immunohistochemistry demonstrated that the principal egr-1 expressing cells in atheromata were mononuclear phagocytes (MP) and smooth muscle cells (SMC). Homozygous egr-1 (0) mice in the apolipoprotein E (apo E) (0) background displayed significantly reduced atherosclerosis at the aortic root compared with apo E (0) animals at 14 or 24 weeks of age. In parallel, transcripts for proinflammatory &procoagulant mediators such as JE/MCP- 1, IL-1beta, VCAM-1, ICAM-1, tissue factor (TF) and PAI-1 were significantly diminished in double (0) mice versus mice solely deficient in apo E (0). To test if the PKCbeta axis, a key upstream regulator of egr-1 in acute hypoxia, modulated regulation of egr-1 in chronic vascular stress, we bred homozygous PKCbeta (0) mice into the apo E (0) background. A striking decrease in atherosclerotic lesion area was evident at age 24 weeks in PKCbeta (0)/apo E (0) vs apo E (0) mice. Levels of plasma glucose and cholesterol/triglyceride did not differ between egr- 1 (0)- or PKCbeta (0)/apo E (0) mice versus apo E (0) animals, thus implicating egr-1 and PKCbeta as distinct facets in atherosclerosis. We hypothesize that PKCbeta-dependent up regulation of egr-1 contributes importantly to acceleration of proinflammatory and prothrombotic mechanisms in the vessel wall;processes linked to the pathogenesis of atherosclerosis. We propose to dissect the biochemical and signaling mechanisms by which PKCbeta and egr-1 contribute to lesion development/progression in hypercholesterolemic apo E (0) mice and anticipate that elucidation of the mechanisms by which these factors impact on atherogenesis may highlight new targets for therapeutic intervention.
| Kong, Linghua; Shen, Xiaoping; Lin, Lili et al. (2013) PKC? promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice. Arterioscler Thromb Vasc Biol 33:1779-87 |
| Harja, Evis; Chang, Jong Sun; Lu, Yan et al. (2009) Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis. FASEB J 23:1081-91 |
| Yan, Shi-Fang; Harja, Evis; Andrassy, Martin et al. (2006) Protein kinase C beta/early growth response-1 pathway: a key player in ischemia, atherosclerosis, and restenosis. J Am Coll Cardiol 48:A47-55 |
