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Murine Cytomegalovirus (MCMV) Infection Upregulates P38 MAP kinase in Aortas of Apo E KO Mice: a Molecular Mechanism for MCMV-Induced Acceleration of Atherosclerosis

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Abstract

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. Aortas of MCMV-infected and uninfected Apo E knockout (KO) mice were analyzed for atherosclerotic lesion development and differential gene expression. Lesions in the infected mice were larger and showed more advanced disease compared to the uninfected mice. Sixty percent of the genes in the MAPK pathway were upregulated in the infected mice. p38 and ERK 1/2 MAPK genes were 5.6- and 2.0-fold higher, respectively, in aortas of infected vs. uninfected mice. Levels of VCAM-1, ICAM-1, and MCP-1 were ~2.0–2.6-fold higher in aortas of infected vs. uninfected mice. Inhibition of p38 with SB203580 resulted in lower levels of pro-atherogenic molecules and MCMV viral load in aortas of infected mice. MCMV-induced upregulation of p38 may drive the virus-induced acceleration of atherogenesis observed in our model.

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Acknowledgments

The authors thank the Lucy Whittier Molecular Core Facility at the School of Veterinary Medicine, UC Davis, for excellent technical assistance with the RNA extraction and cDNA synthesis. We are grateful to Mr. Matthew Rolston at the UC Davis School of Medicine DNA Microarray Core Facility for assistance with the DNA microarray analyses.

This work was supported in part by an Innovative Development Award (YTF) from UC Davis Academic Federation and by grant UL1 RRO24146 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Road Map for Medical Research (CP), and the Frances Lazda Endowment in Women’s Cardiovascular Medicine (ACV).

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Authors and Affiliations

  1. Department of Internal Medicine, University of California, Davis, Sacramento, CA, 95817, USA

    Yajarayma J. Tang-Feldman, Stephanie R. Lochhead, G. Raymond Lochhead, Amparo C. Villablanca & Claire Pomeroy

  2. Department of Pathology, University of California, Davis, Sacramento, CA, 95817, USA

    Cindy Yu

  3. Department of Medical Microbiology and Immunology, University of California, Davis, Sacramento, CA, 95817, USA

    Michael George

  4. Department of Internal Medicine and Department of Medical Microbiology and Immunology, University of California, Davis, Sacramento, CA, 95817, USA

    Claire Pomeroy

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  1. Yajarayma J. Tang-Feldman
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Correspondence to Yajarayma J. Tang-Feldman or Claire Pomeroy.

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Supplementary Figure 1

Canonical signaling pathways upregulated in Apo E Knockout mice compared to wild-type, C57BL/6. Figure is generated by the Ingenuity Pathway Analysis Software. (JPEG 143 kb)

Supplementary Figure 2

Effect of p38 inhibitor, SB203580, on c-Raf/MEK/ERK1/2 pathway. a mRNA levels of c-Raf in aortas of MCMV-infected, SB203580 treated and untreated Apo E KO mice; b mRNA levels of Map2K1 in aortas of MCMV-infected, SB203580 treated and untreated Apo E KO mice; c mRNA levels of ERK1/2 in aortas of MCMV-infected, SB203580 treated and untreated Apo E KO mice. (n = 5 mice treated vs. untreated). Mice were treated as described in “Materials and Methods”. (JPEG 25 kb)

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Tang-Feldman, Y.J., Lochhead, S.R., Lochhead, G.R. et al. Murine Cytomegalovirus (MCMV) Infection Upregulates P38 MAP kinase in Aortas of Apo E KO Mice: a Molecular Mechanism for MCMV-Induced Acceleration of Atherosclerosis. J. of Cardiovasc. Trans. Res. 6, 54–64 (2013). https://doi.org/10.1007/s12265-012-9428-x

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