TY - JOUR
T1 - Human cytomegalovirus induces upregulation of arginase II
T2 - Possible implications for vasculopathies
AU - Yaiw, Koon Chu
AU - Mohammad, Abdul Aleem
AU - Taher, Chato
AU - Wilhelmi, Vanessa
AU - Davoudi, Belghis
AU - Strååt, Klas
AU - Assinger, Alice
AU - Ovchinnikova, Olga
AU - Shlyakhto, Eugene
AU - Rahbar, Afsar
AU - Koutonguk, Oksana
AU - Religa, Piotr
AU - Butler, Lynn
AU - Khan, Zahidul
AU - Streblow, Daniel
AU - Pernow, John
AU - Söderberg-Nauclér, Cecilia
N1 - Funding Information:
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.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Arginase
KW - Cytomegalovirus
KW - Immediate early gene
KW - Nitric oxide synthase
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U2 - 10.1007/s00395-014-0401-5
DO - 10.1007/s00395-014-0401-5
M3 - Article
C2 - 24442486
AN - SCOPUS:84892397366
SN - 0300-8428
VL - 109
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 2
M1 - 401
ER -