Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells.
In viral myocarditis, adeno- and enteroviruses have most commonly been implicated as causes of infection. Both viruses require the human coxsackie-adenovirus receptor (CAR) to infect the myocardium. Due to its crucial role for viral entry, CAR-downregulation may lead to novel approaches for treatment for viral myocarditis. In this study, we report on pharmaceutical drug influences on CAR levels in human umbilical vein endothelial cells (HUVEC) and cervical carcinoma cells (HeLa) detected by immunoblotting, quantitative real time-PCR and cellular susceptibility to the cardiotropic coxsackie-B3 virus strain Nancy (CVB3). Our results indicate, for the first time, a dose-dependent CAR mRNA and protein downregulation upon Valsartan and Bosentan treatment. Most interestingly, drug-induced CAR diminution significantly reduced the viral load in CVB3-infected HUVEC. In order to assess the regulatory effects of both drugs in detail, we knocked down their protein targets, the G-protein coupled receptors angiotensin-II type-1 receptor (AT(1)R) and endothelin-1 type-A and -B receptors (ET(A)R/ET(B)R) in HUVEC. Receptor-specific gene silencing indicates that CAR gene expression is regulated by agonistic and antagonistic binding to ET(B)R, but not ET(A)R. In addition, neither stimulation nor inhibition of AT(1)R seemed to be involved in CAR gene regulatory processes. Our study indicates that Valsartan and Bosentan protected human endothelial cells from CVB3-infection. Therefore, besides their well-known anti-hypertensive effects these drugs may also protect the myocardium and other tissues from coxsackie- and adenoviral infection.
Funke
Carsten
C
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
Farr
Martin
M
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
Werner
Bianca
B
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
Dittmann
Sven
S
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
Überla
Klaus
K
Department of Molecular and Medical Virology, Ruhr University of Bochum, Universitätsstr. 150, 44801 Bochum, NRW, Germany.
Piper
Cornelia
C
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
Niehaus
Karsten
K
Center for Biotechnology (CeBiTec), Bielefeld University, Universitätsstr. 27, 33615 Bielefeld, NRW, Germany.
Horstkotte
Dieter
D
Department of Cardiology, Heart and Diabetes Center NRW, Ruhr University of Bochum, Georgstr. 11, 32545 Bad Oeynhausen, NRW, Germany.
D000998:Antiviral Agents / Q000494:pharmacology*; D000077300:Bosentan; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015536:Down-Regulation; D042783:Endothelial Cells / Q000821:virology*; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000502:physiology; D004847:Epithelial Cells / Q000821:virology; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D012333:RNA, Messenger; D011991:Receptors, Virus; D013449:Sulfonamides; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D000077300:Bosentan