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

Dai Yamanouchi, Stephanie Morgan, Kaori Kato, Justin Lengfeld, Fan Zhang, Bo Liu

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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. Conclusion: These results indicate that medial SMC apoptosis may contribute to vascular inflammation and thus aneurysm formation, in part through production of MCP-1.

Original languageEnglish (US)
Pages (from-to)702-707
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Aneurysms
  • Angiotensin II
  • Apoptosis
  • MCP-1
  • Migration

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