Inhibition of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production suppressed the intimal hyperplasia caused by poor-runoff conditions in the rabbit autologous vein grafts

The efficacy of OPC-29030, a newly developed inhibitor of 12(S)-hydroxyeico satetraenoic acid (12-HETE) production. was evaluated on intimal hyperplasi a of experimental autologous vein grafts in a distal poor-runoff model and a hyperlipidemic model in rabbits. First, rabbits were divided into two gro ups, the distal poor-runoff group (PR group) and the hyperlipidemic group ( HL group). After 4 weeks preparing the PR model and the HL model, the femor al vein was implanted into the ipsilateral femoral artery. Then they were s ubdivided into two groups, depending on the diet provided; diet group with 0.1% OPC-29030 (OPC-29030 group) and normal diet group (control group). At 4 weeks, the grafts were harvested, and intimal hyperplasia of the graft wa s measured with an ocular cytometer. Intimal cell proliferation was determi ned by bromodeoxyuridine (BrdU) incorporation at 2 weeks after surgery. In addition, the effect of OPC-29030 on the proliferation or migration of rat aortic smooth muscle cells in culture was investigated. In the in vivo stud y in the PR group, the intimal hyperplasia and the plasma 12-HETE levels in the OPC-29030 group were significantly inhibited, compared with those of t he control group. However, in the HL group, the intimal hyperplasia in both the OPC-29030 and control groups showed a remarkable degree of intimal hyp erplasia. There was no significant difference between those two groups. Fur thermore, there was no significant difference in the plasma 12-HETE levels in the HL group irrespective of the presence of OPC-29030. The BrdU labelin g index at 2 weeks after grafting was significantly lower in the OPC-29030 group compared with that in the control group in the PR group. In the in vi tro study, OPC-29030 did not inhibit smooth muscle cell proliferation; howe ver, OPC-29030 inhibited the migration. These results demonstrate the effic acy of OPC-29030 in reducing the degree of intimal hyperplasia under PR con ditions, but not under hyperlipidemic conditions. The mechanism of reducing the intimal hyperplasia may be that OPC-29030 inhibited 12-HETE production , which did not inhibit proliferation while inhibiting migration of the smo oth muscle cell. These results suggested the possible involvement of 12-HET E with the intimal hyperplasia under PR conditions.