Abstract 17139: Cathepsin S Deficiency Attenuates AngiotensinII-induced Abdominal Aortic Aneurysm Without Altering Hypertension in ApoE Knockout Mice

Abstract

Abdominal aortic aneurysm (AAA) formation is characterized by weakening of the vessel wall, followed by progressive expansion and eventual rupture of the diseased aortic segment. Extracellular matrix remodeling contributes importantly to the pathogenesis of cardiovascular diseases such as atherosclerosis and abdominal aortic aneurysms. The cysteine protease, cathepsin is one of the most potent mammalian elastases and collagenases, which were highly expressed in the AAA wall compared to that in healthy arteries. Here, we examined the hypothesis that Cat S and Cat K plays a key role in AAA formation. When infused with Angiotensin II (Ang II; 1 μg/kg/min) using osmotic pumps for 28 days, 69% of ApoE KO mice (9 of 13 mice), 75% of Cat K_ApoE DKO (6 of 8 mice) and only 7% of Cat S_ApoE DKO (1 of 13 mice) developed AAA as determined by increases in abdominal aorta diameter by more than two-fold above control. In mice infused with angiotensin II, mortality due to aortic rupture occurred more frequently in ApoE KO mice (4 of 13 mice; 30%) compared to Cat K_ApoE DKO mice (1 of 8mice; 12.5%) and Cat S_ApoE DKO mice (1 of 13 mice; 7%). AngII infusion also significantly increased systemic blood pressure (155-165 mmHg) in ApoE KO mice (n=13), Cat K_ApoE DKO (n=8) and Cat S_ApoE DKO (n=13) mice but, there are no significant difference between the groups. Our results showed that Cat K gene deficiency does not affect AAA development while Cat S gene deficiency dramatically prevented Ang II-induced AAA formation without altering hypertension. These data suggest that Cat S plays a central role in AAA development. Targeting the Cat S may lead to an important therapeutic intervention for preventing AAA formation