Abstract 518: Microtubule-stabilizing Drug Epothilone D Protects Mice From Angiotensin II-induced Abdominal Aortic Aneurysmal Rupture

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 43; no. Suppl_1
• Main Authors: Frony, Ana Clara S, Javidan, Aida, Jiang, Weihua, Yang, Lihua, Subramanian, Venkateswaran
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.43.suppl_1.518

Abstract only Background and Objective: Abdominal aortic aneurysms (AAAs) are permanent dilations of the aorta with 80% mortality after rupture. AAA is associated with the destruction of aortic vascular cellular components including cellular cytoskeleton. Microtubules are heterodimers of globular proteins- α- and β- tubulins, which form a major part of the cellular cytoskeleton and provide stability to cell structure and shape. Microtubule stabilization is emerging as an effective approach to improve cell cytoskeletal stability under various disease conditions. Currently, the functional contribution of cellular microtubule stabilization in AAA development is not known. The purpose of this study is to examine the effect of an FDA-approved microtubule-stabilizing drug, Epothilone D (EpoD) on Angiotensin II (AngII)-induced AAA formation in mice. Methods and Results: To examine microtubule protein distribution in AAAs, human and AngII-induced mouse AAAs and non-aneurysmal abdominal aorta (NAA) were immunostained using antibodies against microtubule protein, α- tubulin. Immunostaining analyses revealed that both human and mouse AAAs are associated with decreased α- tubulin protein compared to NAAs. To examine the effect of the microtubule-stabilizing drug, EpoD on AngII-induced AAA formation, male LDL receptor -/- mice (16 weeks old; n=10 per group) were fed a fat-enriched diet (21% fat; 0.15% cholesterol) for 5 weeks. The vehicle or microtubule-stabilizing drug, EpoD (3 or 10 mg/kg, i.p.) was administered twice a week for 5 weeks. After 1 week of diet feeding and EpoD dosing, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. EpoD administration had no significant effect on AngII-induced AAA expansion as measured by ex vivo diameter (Vehicle: 1.50 ± 0.30 mm vs EpoD (3 mg/kg): 1.90 ± 0.70 mm; EpoD (10 mg/kg): 1.40 ± 0.20 mm; P = 0.58). EpoD administration significantly suppressed AngII-induced AAA rupture in a dose-dependent manner compared to the vehicle group (AAA Rupture: Vehicle: 70% versus EpoD (3mg/kg): 20%; EpoD (10mg/kg): 0%, P<0.05, respectively). Conclusion: These findings demonstrate that microtubule stabilization by EpoD significantly suppresses AngII-induced AAA rupture without influencing AAA formation in mice.