title: Human Cytomegalovirus Up-Regulates Endothelin Receptor Type B: Implication for Vasculopathies?
abstract: Background.  Both endothelin receptor type B ([ETBR], a G protein-coupled receptor that mediates the vascular effects of the potent vasoconstrictor endothelin-1) and human cytomegalovirus ([HCMV], a ubiquitous herpesvirus) have been implicated in the pathogenesis of cardiovascular disease (CVD). The effects of HCMV infection on ETBR expression are unknown. We hypothesized that HCMV may contribute to the pathogenesis of CVD via ETBR modulation. Methods.  Human CMV effects on ETBR were studied in vitro in endothelial cells (ECs) and smooth muscle cells (SMCs) and ex vivo in human carotid plaque tissue specimens. Expression of ETBR and viral immediate-early were quantified using quantitative polymerase chain reaction. Functional consequences after ETBR blockade in ECs were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide proliferation, wound healing, tube formation, and flow adhesion assays. Results.  Human CMV is capable of upregulating both ETBR mRNA and protein expression in ECs and SMCs. The ETBR was also abundantly expressed in ECs, foam cells, and SMCs, and, more importantly, in HCMV-positive cells in human carotid plaques. Endothelin receptor type B blockade led to decreased proliferation and reduced tumor necrosis factor α-mediated leukocyte recruitment in both uninfected and HCMV-infected ECs. Direct HCMV infection was antimigratory and antiangiogenic in ECs. Conclusions.  Human CMV may contribute to CVD via ETBR induction.
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Koon-Chu
authors.initials: KC
authors.lastname: Yaiw
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Abdul-Aleem
authors.initials: AA
authors.lastname: Mohammad
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Helena
authors.initials: H
authors.lastname: Costa
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Chato
authors.initials: C
authors.lastname: Taher
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet ; Center for Physiology and Pharmacology , Institute of Physiology, Medical University of Vienna , Austria.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Badrnya
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet ; Center for Physiology and Pharmacology , Institute of Physiology, Medical University of Vienna , Austria.
authors.forename: Alice
authors.initials: A
authors.lastname: Assinger
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wilhelmi
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Sharan
authors.initials: S
authors.lastname: Ananthaseshan
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Atosa
authors.initials: A
authors.lastname: Estekizadeh
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Belghis
authors.initials: B
authors.lastname: Davoudi
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Olga
authors.initials: O
authors.lastname: Ovchinnikova
authors.affiliation: Almazov Federal Heart, Blood and Endocrinology Centre , St . Petersburg , Russia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Shlyakhto
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet ; Department of Medicine, Cardiology Unit , Karolinska University Hospital Solna , Stockholm , Sweden.
authors.forename: Arnar
authors.initials: A
authors.lastname: Rafnsson
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Zahidul
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Lynn
authors.initials: L
authors.lastname: Butler
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet ; Department of Medicine, Cardiology Unit , Karolinska University Hospital Solna , Stockholm , Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Pernow
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Microbial Pathogenesis Unit , Karolinska University Hospital, Karolinska Institutet.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
keywords: BQ788; angiogenesis; cytomegalovirus; endothelial cells; endothelin receptor type B; leukocyte recruitment; vasculopathies