1311. Molecular Mechanisms of Murine Cytomegalovirus (MCMV)-Induced Acceleration of Atherosclerosis:  Role of the Mitogen Activated Protein Kinase Pathway
Session: Poster Abstract Session: Viral Immunology and Pathogenesis
Saturday, October 22, 2011
Room: Poster Hall B1
Background: 

Multiple studies suggest an association between cytomegalovirus (CMV) infection and atherogenesis; however, the molecular mechanisms by which viral infection might exacerbate atherosclerosis are not well understood.    In this study, we demonstrate that activation of genes in the Mitogen Activated Protein Kinase (MAPK) pathway , specifically p38 and ERK 1/2 , by MCMV infection is associated with acceleration of atherosclerosis. 

Methods: 

Apo E knockout (KO) mice were infected with a sub-lethal dose of MCMV.  Aortas were dissected and sections analyzed for atherosclerotic lesion complexity and staging using ORO lipid staining.  RNA from aortas of infected and uninfected mice were analyzed by DNA microarray.  Gene families/pathways were identified and selected genes were validated by real-time PCR and Western blot analysis.  

Results: 

DNA microarray analysis of lesions in aortas of MCMV-infected vs. uninfected Apo E KO mice at early stages of atherosclerosis demonstrated up-regulation of 90% of genes in the MAPK pathway, especially p38 and ERK 1/2.  Validation by real time PCR showed that p38 and ERK 1/2 were 6 and 66-fold higher respectively in aortas of infected vs. uninfected mice.  Similar impact on protein expression was confirmed by Western blot analysis.   In concert with over-expression of p38 and ERK 1/2, lesions in the infected mice showed more advanced disease, with complex atheromas and intima fibrosis (stage V-VI) compared to only fatty streak and lipid accumulation in the uninfected mice (stage II and III).   Using a green fluorescence labeled MCMV,  we demonstrated dissemination of CMV to the vascular wall and plaque lesions.      

Conclusion: 

1) MCMV infection upregulates p38 and ERK 1/2 , important MAPK genes expressed in viral infection;  2) MCMV infection accelerates atherosclerotic plaque progression, with earlier development of severe lesions.  To our knowledge, this is the first report showing a direct correlation of virus induced upregulation of genes in the MAPK pathway and  atherosclerosis. Because p38 and ERK 1/2 are known to promote foam cell formation and secretion of pro-inflammatory mediators, we conclude that MCMV-induced upregulation of these genes may drive the virus-induced acceleration of atherogenesis observed in our model. 


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

Yajarayma Tang Feldman, MA1, Stephanie Lochhead, BS1, G Raymond Lochhead, BS1, Cindy Q. Yu, MD2, Michael George, PhD3 and Claire Pomeroy, MD, MBA4, (1)Internal Medicine, Infectious Diseases, University of California, Davis Health System, Sacramento, CA, (2)Pathology, University of California, Davis Health System, Sacramento, CA, (3)Medical Microbiology and Immunology, University of California, Davis, Davis, CA, (4)Internal Medicine, University of California, Davis Health System, Sacramento, CA

Disclosures:

Y. Tang Feldman, None

S. Lochhead, None

G. R. Lochhead, None

C. Q. Yu, None

M. George, None

C. Pomeroy, None

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