title: Human cytomegalovirus-induced reduction of extracellular matrix proteins in vascular smooth muscle cell cultures: a pathomechanism in vasculopathies?
abstract: Human cytomegalovirus (HCMV) infection appears to be linked to the pathogenesis of atherosclerosis. An association between HCMV infection and an enhanced restenosis rate as well as the induction of vasculopathies after solid organ transplantation has been documented. Knowledge of the cellular and molecular basis of these findings is limited, however. By Northern blot and RT-PCR analysis of human foreskin fibroblasts (HFF) and human coronary artery smooth muscle cells (SMC), we identified extracellular matrix (ECM) genes that were downregulated after HCMV infection, including collagen type I and fibronectin. Quantitative immunoassays showed a significant reduction of soluble collagen type I and fibronectin proteins in supernatants of both cell types. This was shown to be a direct effect of HCMV infection and not due to a response to interferons released from infected cells, since neutralization of alpha and beta interferon activity could not block virus-induced downregulation of matrix proteins. As the amount of ECM depends on both synthesis and degradation, we also assessed the influence of HCMV on the activity of matrix metalloproteinases (MMP). Interestingly, a significant difference in virus-induced matrix degradation could be shown between the two cell types. HCMV upregulated MMP-2 protein and activity in SMC but not in HFF. Thus, HCMV infection of SMC reduces ECM dramatically by inducing two independent mechanisms that influence synthesis as well as degradation of ECM. These may represent molecular mechanisms for HCMV-induced pathogenesis of inflammatory vasculopathies and may facilitate dissemination of HCMV by promoting the detachment of infected cells in vivo.
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Reinhardt
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schaarschmidt
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Pretsch
authors.affiliation: Department of Clinical Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Vaida
authors.affiliation: Department of Clinical Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schmid-Kotsas
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Michel
authors.affiliation: Central Electron Microscopy Facility, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Department of Clinical Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Bachem
authors.affiliation: Institute of Virology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mertens
mesh_terms: D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000472:pathogenicity* / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D024022:Fibrillar Collagens / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism / Q000473:pathology* / Q000821:virology*
chemical_list: D016326:Extracellular Matrix Proteins; D024022:Fibrillar Collagens; D005353:Fibronectins; D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2