FK778 Attenuates Cytomegalovirus-Enhanced Vein Graft Intimal Hyperplasia in a Rat Model

Abstract

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 × 10⁶ 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.

The inhibitors of nucleotide biosynthesis leflunomide, FK778, and mycophenolic acid activate hepatitis B virus replicationin vitro

“…In addition, both A771726 and FK778 can block human cytomegalovirus (CMV) replication 6. In view of this antiviral activity, FK778 has been proposed to bear potential for preventing CMV‐associated intimal hyperplasia, which is a major complication in vein grafts used for the treatment of coronary artery disease 7. Furthermore, leflunomide and/or FK778 have been reported to repress the replication of several other viruses, such as herpes simplex virus type‐1 (HSV‐1),8 human immunodeficiency virus‐1 (HIV‐1),9 and respiratory syncytial virus (RSV) 10.…”

“Venopathy” at work: recasting neointimal hyperplasia in a new light

“…Alternatively, different agents could be tried as therapeutics to regulate NH. The novel immunosuppressive agent, FK778, exerts an anti-proliferative effect on multiple cell types, limiting NH in vein graft models (45, 46). …”