title: Differential regulation of matrix metalloproteinases in varicella zoster virus-infected human brain vascular adventitial fibroblasts.
abstract: Upon reactivation, varicella zoster virus (VZV) spreads transaxonally, infects cerebral arteries and causes ischemic or hemorrhagic stroke, as well as aneurysms. The mechanism(s) of VZV-induced aneurysm formation is unknown. However, matrix metalloproteinases (MMPs), which digest extracellular structural proteins in the artery wall, play a role in cerebral and aortic artery aneurysm formation and rupture. Here, we examined the effect of VZV infection on expression of MMP-1, -2, -3, and -9 in primary human brain vascular adventitial fibroblasts (BRAFS). At 6 days post-infection, VZV- and mock-infected BRAFs were analyzed for mRNA levels of MMP-1, -2, -3 and -9 by RT-PCR and for corresponding total intra- and extracellular protein levels by multiplex ELISA. The activity of MMP-1 was also measured in a substrate cleavage assay. Compared to mock-infected BRAFs, MMP-1, MMP-3 and MMP-9 transcripts, cell lysate protein and conditioned supernatant protein were all increased in VZV-infected BRAFs, whereas MMP-2 transcripts, cell lysate protein and conditioned supernatant protein were decreased. MMP-1 from the conditioned supernatant of VZV-infected BRAFs showed increased cleavage activity on an MMP-1-specific substrate compared to mock-infected BRAFs. Differential regulation of MMPs in VZV-infected BRAFs may contribute to aneurysm formation in VZV vasculopathy.
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: maria.nagel@ucdenver.edu.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Nagel
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Choe
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: April
authors.initials: A
authors.lastname: Rempel
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Wyborny
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Stenmark
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Gilden
mesh_terms: D063194:Adventitia / Q000378:metabolism / Q000821:virology; D018929:Cell Culture Techniques; D002539:Cerebral Arterial Diseases / Q000378:metabolism / Q000821:virology; D005333:Fetus; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006562:Herpes Zoster / Q000378:metabolism / Q000821:virology; D014645:Herpesvirus 3, Human / Q000472:pathogenicity*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*
chemical_list: D020782:Matrix Metalloproteinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Aneurysm; Matrix metalloproteinases; Varicella zoster virus vasculopathy