Inhibition of rho-kinase by fasudil suppresses formation and progression of experimental abdominal aortic aneurysms.

Abstract

OBJECTIVE: Accumulating evidence suggests that inflammatory cell infiltration is crucial pathogenesis during the initiation and progression of abdominal aortic aneurysm (AAA). Given Rho-kinase (ROCK), an important kinase control the actin cytoskeleton, regulates the inflammatory cell infiltration, thus, we investigate the possibility and mechanism of preventing experimental AAA progression via targeting ROCK in mice porcine pancreatic elastase (PPE) model. METHODS AND RESULTS: AAA was created in 10-week-old male C57BL/6 mice by transient intraluminal porcine pancreatic elastase infusion into the infrarenal aorta. The mRNA level of RhoA, RhoC, ROCK1 and ROCK2 were elevated in aneurismal aorta. Next, PPE infusion mice were orally administrated with vehicle or ROCK inhibitor (Fasudil at dose of 200 mg/kg/day) during the period of day 1 prior to PPE infusion to day 14 after PPE infusion. PPE infusion mice treated with Fasudil produced significantly smaller aneurysms as compare to PPE infusion mice treated with vehicle. AAAs developed in all vehicle-treated groups within 14 days, whereas AAAs developed in six mice (66%, 6/9) treated with Fasudil within 14 days. Furthermore, our semi-quantitative histological analysis revealed that blood vessels and macrophages were significantly reduced in Fasudil treated mice during the AAA progression. Finally, when mice with existing AAAs were treated with Fasudil, the enlargement was nearly completely suppressed. CONCLUSION: Fasudil inhibits experimental AAA progression and stabilize existing aneurysms, through mechanisms likely related to impaired mural macrophage infiltration and angiogenesis. These findings suggest that ROCK inhibitor may hold substantial translational value for AAA diseases.