FK778 attenuates cytomegalovirus-enhanced vein graft intimal hyperplasia in a rat model.
BACKGROUND
Venous grafts are commonly used to treat drug-resistant coronary artery disease, although long-term functionality is limited because of proliferation and migration of smooth muscle cells (SMC). As proliferating SMC are particularly susceptible for the stimulating effects of cytomegalovirus (CMV), we hypothesized that CMV infection may enhance cell proliferation and graft failure. Furthermore, we evaluated the potential of FK778 to prevent intimal hyperplasia. Apart from its antiviral properties, FK778 is a new immunosuppressive agent which may also affect SMC proliferation, making it an interesting drug to prevent (CMV-enhanced) venous graft intimal hyperplasia.


METHODS
Epigastric vein-to-common femoral artery interposition grafts were placed in four groups of 10 rats each. Rats received either FK778 (oral treatment, 15 mg/kg), were infected with CMV (1.25 x 10(6) plaque-forming units) or were both treated and infected.


RESULTS
CMV infection resulted in a significant increase in intimal and medial cross-sectional area and medial wall thickness of the vein grafts. This effect was diminished by administration of FK778. Moreover, FK778 treatment alone resulted in a significant decrease in neointimal area and percentage of stenosis versus the control group.


CONCLUSIONS
These data suggest a role of CMV in venous graft failure. Also, our results suggest a prospective role for the new immunosuppressive drug FK778 in the prevention of (CMV-mediated) vein graft intimal hyperplasia.
Kloppenburg
Geoffrey
G
Department of Medical Microbiology, University Hospital Maastricht/Maastricht University, Maastricht, The Netherlands. geoffrey_kloppenburg@hotmail.com
de Graaf
Rick
R
Grauls
Gert
G
Bruggeman
Cathrien A
CA
van Hooff
Johannes P
JP
Stassen
Frank
F
D000480:Alkynes / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D006965:Hyperplasia / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D018146:Muromegalovirus / Q000302:isolation & purification*; D009570:Nitriles / Q000627:therapeutic use*; D051381:Rats; D019737:Transplants / Q000009:adverse effects*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D000480:Alkynes; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide