title: Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.
abstract: BACKGROUND
  Major risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated.
  
  
  RESULTS
  Aortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with 10(5) plaque-forming units of RCMV 1 day after transplantation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day for a period of 14 days. In the DHPG prophylaxis group (n = 22), the drug administration started 1 day before infection, and in the DHPG treatment group (n = 17), 7 days after infection. One group of infected rats was left untreated (n = 21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophylaxis group, no virus could be recovered by plaque assays. In the treatment group, 50% of rats were virus-positive at 1 month and 40% at 3 months. DHPG prophylaxis prevented the infiltration of inflammatory cells and their proliferation in the adventitia of RCMV-infected recipients (P < .01), with a 60% reduction in the interleukin-2 receptor expression (P < .05) and a 30% decrease in major histocompatibility complex class II expression (P = NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor-BB, transforming growth factor-beta 1, acidic fibroblast growth factor, and basic fibroblast growth factor messages in the allograft vascular wall. Early media necrosis was reduced. Arteriosclerotic alterations and proliferation of smooth muscle cells were both reduced 50% to 70% by DHPG prophylaxis (P < .05 at 3 months). The responses in the DHPG treatment group were quite similar but less impressive and statistically nonsignificant.
  
  
  CONCLUSIONS
  We consider it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antiproliferative effect on smooth muscle cell replication. A dose-dependent inhibitory effect of DHPG on smooth muscle cell replication was recorded in an in vitro study.
authors.affiliation: Transplantation Laboratory, University of Helsinki, Finland.
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
authors.forename: J H
authors.initials: JH
authors.lastname: Bruning
authors.forename: C A
authors.initials: CA
authors.lastname: Bruggeman
authors.forename: P K
authors.initials: PK
authors.lastname: Koskinen
authors.forename: P T
authors.initials: PT
authors.lastname: Aho
authors.forename: S
authors.initials: S
authors.lastname: Yilmaz
authors.forename: I T
authors.initials: IT
authors.lastname: Lautenschlager
authors.forename: P J
authors.initials: PJ
authors.lastname: Häyry
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000382:microbiology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D016378:Tissue Transplantation; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
chemical_list: D000998:Antiviral Agents; C045895:9-((2,3-dihydroxy-1-propoxy)methyl)guanine; D015774:Ganciclovir