Human Cytomegalovirus Up-Regulates Endothelin Receptor Type B: Implication for Vasculopathies?

• Published in: Open forum infectious diseases 2015-12, Vol.2 (4), p.ofv155-ofv155
• Main Authors: Yaiw, Koon-Chu, Mohammad, Abdul-Aleem, Costa, Helena, Taher, Chato, Badrnya, Sigrun, Assinger, Alice, Wilhelmi, Vanessa, Ananthaseshan, Sharan, Estekizadeh, Atosa, Davoudi, Belghis, Ovchinnikova, Olga, Shlyakhto, Eugene, Rafnsson, Arnar, Khan, Zahidul, Butler, Lynn, Rahbar, Afsar, Pernow, John, Söderberg-Nauclér, Cecilia
• Format: Article
• Language: English
• Subjects: Major
• ISSN: 2328-8957; 2328-8957
• DOI: 10.1093/ofid/ofv155

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.