Abstract 1216: Selective ROCK 2 Inhibition Attenuates Arterial Plaque Formation in an ApoE Knockout Mouse Model
Rho kinases (ROCK 1 and ROCK 2) have been suggested as attractive targets for CV drug development based principally on pharmacological responses to fasudil and Y-27632. These non-selective kinase inhibitors do not discriminate between ROCK 1, ROCK 2 or other kinase targets. Using SLx-2119, an orally bioavailable, potent and highly selective inhibitor of ROCK 2 we have demonstrated reduced atherogenesis in the presence of dramatically elevated lipid levels. Groups of 8 ApoE knockout mice (Taconic Transgenic Model B6.129P2-Apoetm1UncN11), 4 weeks in age, were fed a high-fat diet for 3 weeks prior to daily oral dosing with vehicle, 30 or 100 mg/kg of SLx-2119. After 10 weeks of dosing, the animals were sacrificed and organs were collected for histological evaluation. SLx-2119 treated animals had similar serum HDL, LDL, TC and triglyceride levels when compared to vehicle control animals. Treated mice gained less weight than vehicle control animals; this effect was dose dependent (vehicle control: 11.8 g; 30 mg/kg: 8.6 g (p < 0.05); 100 mg/kg: 5.8 mg/kg (p < 0.01)). All animals were otherwise normal in clinical observations. Histological examination revealed extensive reduction of plaque in the aortic sinus of animals dosed with SLx-2119. Lungs and kidneys from all groups were within normal limits for all animals. The results of this study indicate that previously reported reductions in the formation of arterial plaque following treatment with non-selective Rho kinase inhibitors is the result of their ROCK 2 inhibition and that ROCK 2 inhibition alone has a significant impact on atherogenesis in the presence of elevated lipid levels. Selective ROCK 2 inhibition has the potential to be a new mechanism to limit atherosclerosis and to avoid unwanted hemodynamic side-effects associated with non-selective Rho kinase inhibitors.