1887

Abstract

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 (ATR) and endothelin-1 type-A and -B receptors (ETR/ETR) in HUVEC. Receptor-specific gene silencing indicates that CAR gene expression is regulated by agonistic and antagonistic binding to ETR, but not ETR. In addition, neither stimulation nor inhibition of ATR 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.

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2010-08-01
2019-11-22
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Supplements

vol. , part 8, pp. 1959 - 1970

List of RNA and DNA oligonucleotides

List of applied antibodies, respective dilutions and manufacturers

List of applied drugs, their classification, trademark, manufacturer and (mean) peak plasma concentration (c )

Dose–response curves

Relative expression of CAR mRNA

Western blot analysis of siRNA-treated and control endothelial cells [Single PDF file](338 KB)



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