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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073325-05
Application #
7568212
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
2005-01-15
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
5
Fiscal Year
2009
Total Cost
$343,479
Indirect Cost
Name
Columbia University (N.Y.)
Department
Surgery
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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