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

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.

CONCLUSIONS:

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

• Authors: Dai Yamanouchi, Stephanie Morgan, Kaori Kato, Justin Lengfeld, Fan Zhang, Bo Liu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 4 Pg. 702-7 (Apr 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20075419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Apolipoproteins E
• Caspase Inhibitors
• Ccl2 protein, mouse
• Chemokine CCL2
• Culture Media, Conditioned
• Protease Inhibitors
• Quinolines
• quinoline-val-asp(OMe)-CH2-OPH
• Angiotensin II
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Angiotensin II
• Animals
• Aortic Aneurysm, Abdominal (chemically induced, drug therapy, enzymology, genetics, pathology)
• Apolipoproteins E (deficiency, genetics)
• Apoptosis (drug effects)
• Caspase Inhibitors
• Caspases (metabolism)
• Cells, Cultured
• Chemokine CCL2 (metabolism)
• Chemotaxis (drug effects)
• Culture Media, Conditioned (metabolism)
• Disease Models, Animal
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, enzymology, pathology)
• Myocytes, Smooth Muscle (drug effects, enzymology, pathology)
• Protease Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Severity of Illness Index
• Time Factors