A highly selective inhibitor of Rho-associated coiled-coil forming proteinkinase, Y-27632, prolongs cardiac allograft survival of the BALB/c-to-C3H/He mouse model

Background: Current studies provide evidence that a small G protein, RhoAp2 l, and its target protein, Rho-associated coiled-coil forming protein kinas e (ROCK), regulate not only cell shape but also cell migration. However, co ntribution of Rho/ROCK signaling to graft rejection is unknown. The purpose of this study was to evaluate the inhibitory effect of Y-27632, a highly s elective ROCK inhibitor, on rejection of heterotopic cardiac transplantatio n in mice. Methods: BALB/c (H-2 d) hearts were transplanted into C3H/He (H-2(k)) as al lografts that were full histoincompatibility combinations. The recipients r eceived several doses of Y-27632, commencing 1 day before cardiac transplan tation until rejection. We used inummohistochemical study to detect the exp ression of myocardial intercellular adhesion molecule 1 (ICAM-1) and vascul ar cell adhesion molecule 1 (VCAM-1), and we immunoenzymatically measured s erum interleukin (IL)-6. Furthermore, we evaluated cardiac allograft vascul opathy treated with either FK506 or Y-27632 at Day 100. Results: The Y-27632-treated (2 mg/kg/day) allografts prolonged the mean su rvival time (49.6 +/- 10.1 days, n = 12) as compared with the untreated all ografts (8.1 +/- 0.4 days, n = 7, p < 0.001). Histologic examinations of th e Y-27632-treated allografts at Day 7 showed greatly reduced leukocyte infi ltration compared with the untreated allografts. The Y-27632-treated allogr afts revealed faint expression of myocardial ICAM-1 and VCAM-1 at Day 7. Th e serum IL-6 levels also decreased in the Y-27632-treated mice. In the long -surviving Y-27632-treated allografts at Day 100, we saw neither active rej ection nor apparent thickening of vascular intima. Conclusion: Our results suggest that ROCK plays a major role in cardiac rej ection in the BALB/c-to-C3H/He mouse model. Inhibition of this Rho/ROCK sig naling may be an alternative therapeutic option for managing acute and chro nic rejection.