title: Rat cytomegalovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33.
abstract: Cytomegalovirus (CMV) infection accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in both human and animal solid organ transplantation models. The host/viral mechanisms involved in this process are unclear. We examine the role of the rat CMV (RCMV)-encoded chemokine-receptor R33 in the development of TVS using a rat heart transplantation/CR model. F344 heart grafts were transplanted heterotopically into Lewis recipients. The ability of RCMV lacking the R33 gene (RCMV-Deltar33) to accelerate CR/TVS (neointimal index, NI) was compared to wild-type (WT) RCMV. Allograft recipients were infected with 1 x 10(5) pfu RCMV or RCMV-Deltar33 on postoperative day (POD) 1. Grafts from RCMV-Deltar33-infected recipients demonstrated an accelerated time to allograft CR compared to grafts from uninfected recipients (POD = 56 vs. 90), this was slower than that seen in grafts from WT-RCMV-infected recipients (POD = 45). Similarly, the degree of graft TVS formation at terminal rejection in RMCV-Deltar33 infected recipients was more severe than uninfected recipients (NI = 63 vs. 45), yet not as severe as in WT-RCMV infected recipients (NI = 83). In parallel, RCMV-Deltar33 failed to induce vascular smooth muscle cell (SMC) migration in vitro, whereas WT-RCMV induced substantial migration. The RCMV-encoded chemokine-receptor r33 is critical for RCMV-accelerated TVS/CR and vascular SMC migration.
authors.affiliation: Department of Molecular Microbiology and Immunology and The Vaccine and Gene Therapy Institute, Oregon Health Sciences University, Portland, OR 97239, USA. streblow@ohsu.edu
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Streblow
authors.forename: Craig N
authors.initials: CN
authors.lastname: Kreklywich
authors.forename: Patricia
authors.initials: P
authors.lastname: Smith
authors.forename: Jordana L
authors.initials: JL
authors.lastname: Soule
authors.forename: Christine
authors.initials: C
authors.lastname: Meyer
authors.forename: Michael
authors.initials: M
authors.lastname: Yin
authors.forename: Patrick
authors.initials: P
authors.lastname: Beisser
authors.forename: Cornelis
authors.initials: C
authors.lastname: Vink
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Orloff
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000378:metabolism / Q000821:virology*; D003587:Cytomegalovirus / Q000235:genetics* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D016027:Heart Transplantation; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C110721:R33 protein, rat cytomegalovirus; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins