Human cytomegalovirus induces upregulation of arginase II: possible implications for vasculopathies.
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.
Department of Medicine, Center for Molecular Medicine (CMM) L8:03, Karolinska Institutet, 171 76, Stockholm, Sweden, koon.yaiw@ki.se.
Koon-Chu
KC
Yaiw
Abdul-Aleem
AA
Mohammad
Chato
C
Taher
Vanessa
V
Wilhelmi
Belghis
B
Davoudi
Klas
K
Strååt
Alice
A
Assinger
Olga
O
Ovchinnikova
Eugene
E
Shlyakhto
Afsar
A
Rahbar
Oksana
O
Koutonguk
Piotr
P
Religa
Lynn
L
Butler
Zahidul
Z
Khan
Daniel
D
Streblow
John
J
Pernow
Cecilia
C
Söderberg-Nauclér
D000998:Antiviral Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000821:virology; D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000821:virology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D014657:Vasculitis / Q000201:enzymology* / Q000473:pathology / Q000821:virology*
D000998:Antiviral Agents; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C477631:ARG2 protein, human; D001119:Arginase; D015774:Ganciclovir