Effects of caspase inhibitor on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice.

OBJECTIVE The presence of apoptotic markers is a prominent histological feature of abdominal aortic aneurysm. To understand the role of apoptosis in the pathogenesis of this common vascular disease, we tested the effect of the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (Q-VD-OPh) on aneurysm formation using a mouse angiotensin II (Ang II) model. METHODS AND RESULTS Ang II in apolipoprotein E-deficient mice significantly induced medial cell apoptosis 3 days after infusion at the aortic region, eventually becoming aneurismal. A daily administration of 20 mg/kg per day Q-VD-OPh starting 6 hours before Ang II infusion reduced aneurysm incidence from 83.3% to 16.7% and maximal aortic diameter from 2.43+/-0.29 mm to 1.58+/-0.18 mm. The caspase inhibitor treated mice showed profoundly diminished levels of medial apoptosis and inflammation. In contrast, administration of Q-VD-OPh starting 7 days after Ang II infusion had no significant impact on aneurysm development. In vitro, media conditioned by Ang II-treated smooth muscle cells (SMCs) stimulated macrophage chemotaxis in a caspase-dependent manner. Inhibition of monocyte chemoattractant protein-1 (MCP-1) in the conditioned media via a neutralizing antibody completely blocked the ability of conditioned media to attract macrophages. CONCLUSIONS These results indicate that medial SMC apoptosis may contribute to vascular inflammation and thus aneurysm formation, in part through production of MCP-1.