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.


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.
Yamanouchi
Dai
D
Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, 1111 Highland Avenue, WIMR 5120, Madison, WI 53705, USA.
Morgan
Stephanie
S
Kato
Kaori
K
Lengfeld
Justin
J
Zhang
Fan
F
Liu
Bo
B
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012720:Severity of Illness Index; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D001057:Apolipoproteins E; D061945:Caspase Inhibitors; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D011480:Protease Inhibitors; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; D000804:Angiotensin II; D020169:Caspases