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Human cytomegalovirus induces upregulation of arginase II: possible implications for vasculopathies

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Abstract

Both human cytomegalovirus (HCMV) and arginase II (ARG II) have been implicated in the pathogenesis of cardiovascular diseases. The effects of HCMV on ARG II are unknown. The aim of this study was to investigate the effects of HCMV on ARG II expression in endothelial and vascular smooth muscle cells (SMC) both in vitro and ex vivo. Endothelial and SMC were infected with either HCMV or UV-irradiated HCMV. Expression of ARG II, endothelial or inducible nitric oxide synthase (eNOS and iNOS, respectively) and viral immediate early (IE) was quantified using quantitative PCR. Ganciclovir and short interfering RNA were used to determine the viral gene mediating the effects on ARG II. Detection of viral antigens and ARG II expression was performed by immunofluorescence or immunohistochemistry. HCMV infection increased both ARG II mRNA and protein levels in the examined cells; this effect was mediated by the HCMV IE2-p86 protein. The upregulation of ARG II was accompanied by a downregulation of eNOS but an induction of iNOS in HCMV-infected endothelial cells. Both eNOS and iNOS expressions were induced in HCMV-infected SMC. ARG II was abundantly expressed in endothelial cells, foam cells and SMC and was importantly significantly upregulated in HCMV-immunoreactive human carotid atherosclerotic plaques. HCMV IE2-p86 mediates ARG II upregulation in vitro and ARG II is co-expressed with HCMV antigens in human carotid atherosclerotic plaques. We speculate that HCMV may contribute to endothelial dysfunction via ARG II induction and reduced eNOS production.

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Acknowledgments

We thank Charlotte Tammik, the late Maria Ekström and Jessica Petterson for their excellent technical assistance. We are indebted to Drs. Vladimir V. Shlomin, Michail L. Gordeev and Vera A. Ovchinnikova for their assistance in collecting carotid plaques. We would like to thank Robert M. Badeau, Ph.D. for proofreading this manuscript’s English language content. This work was supported by Swedish Heart and Lung Foundation (Grant No. 20100614, 20100259), the Swedish Medical Research Foundation (K2010-56X-12615-13-3, K2012-64X-10857-19-5), CERIC, EU WP7 BASTION and the Cardiovascular Program and Stockholm County Council, Sten A Olssons Foundation, Biltema Foundation, Torsten Söderbergs Foundation, IngaBritt and Arne Lundbergs Foundation, Petrus and Augusta Hedlunds Foundation, nxt2b and Stichting af Jochnicks Foundation.

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Authors and Affiliations

  1. Department of Medicine, Center for Molecular Medicine (CMM) L8:03, Karolinska Institutet, 171 76, Stockholm, Sweden

    Koon-Chu Yaiw, Abdul-Aleem Mohammad, Chato Taher, Vanessa Wilhelmi, Belghis Davoudi, Olga Ovchinnikova, Afsar Rahbar, Piotr Religa, Lynn Butler, Zahidul Khan, John Pernow & Cecilia Söderberg-Nauclér

  2. Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden

    Klas Strååt

  3. Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Alice Assinger

  4. Almazov Federal Center for Heart, Blood and Endocrinology, St. Petersburg, Russia

    Olga Ovchinnikova & Eugene Shlyakhto

  5. Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland

    Oksana Koutonguk

  6. Department of Molecular Microbiology and Immunology and The Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, 97239, USA

    Daniel Streblow

  7. Department of Medicine, Cardiology Unit, Karolinska Institutet, 171 76, Stockholm, Sweden

    John Pernow

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395_2014_401_MOESM1_ESM.tif

Effects of human herpes simplex virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) on arginase II (ARG II) mRNA expression and morphology of endothelial cells at 3-day post-infection. A Relative expression of ARG II with indicated multiplicity of infection (moi) of HSV-1 or HSV-2 as assayed by quantitative TaqMan PCR. B Representative photomicrograpic of HSV-1, HSV-2 and HCMV-infected HUVEC (biological replicate, n = 3, with technical duplicates for each PCR; values are mean ± SD; *p = 0.01-0.05; **p = 0.001-0.01; ***p < 0.001; n.s = not significant; moi = multiplicity of infection) (TIFF 5824 kb)

395_2014_401_MOESM2_ESM.tif

MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay to determine cytotoxicity of HCMV infection on endothelial cells, HUVEC at 1-, 3- and 5-day post-infection (dpi). moi = multiplicity of infection (TIFF 3665 kb)

395_2014_401_MOESM3_ESM.tif

Selected cDNA microarray data on rat heart transplants from latently rat cytomegalovirus-infected or uninfected donor hearts performed with Illumina RatRef-12 arrays containing > 22,000 probes selected from the NCBI RefSeq database. The fold change was determined by dividing expression of infected over uninfected gene of interest. Arg1 = arginase 1; Arg2 = arginase 2; nNOS = neuronal nitric oxide synthase; iNOS = inducible nitric oxide synthase; eNOS = endothelial nitric oxide synthase (TIFF 1740 kb)

395_2014_401_MOESM4_ESM.tif

Aortic ring assay performed on aorta obtained from murine cytomegalovirus (MCMV)-infected APOE knock-out mouse. The number of newly growth vessels or length of sprouting vessels was measured by Adobe Photoshop. Number of mice in each group = 5 (TIFF 1411 kb)

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Yaiw, KC., Mohammad, AA., Taher, C. et al. Human cytomegalovirus induces upregulation of arginase II: possible implications for vasculopathies. Basic Res Cardiol 109, 401 (2014). https://doi.org/10.1007/s00395-014-0401-5

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