Abstract 11917: Effects of Long Term Autophagy Inhibition With Chloroquine on the Development and Progression of Experimental Abdominal Aortic Aneurysms
Introduction: Autophagy is an essential regulator of cellular homeostasis and serves to optimize and integrate cellular pro-survival machinery. We sought to determine the role of autophagy in the natural history of aortic aneurysms (AAA) in mice.
Methods: ApoE-/- mice were implanted with miniosmotic pumps containing either saline or angiotensin II (Ang-II). Mice were subsequently subdivided and administered either the potent autophagy inhibitor chloroquine (CQ, 50 mg/kg/day, i.p.) or saline for 8 weeks. Mortality rates, hemodynamics and abdominal aortic diameters were recorded over the entire monitoring window. Necropsy evaluations, histological and immunohistological staining for aortic wall remodelling, markers of autophagy and inflammation were conducted on suprarenal aortic samples.
Results: Ang-II infusion elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation. CQ had no impact on the incidence (Ang-II: 50.0% vs. Ang-II+CQ: 46.2%, P=NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (Ang-II:57.1% vs. saline:100%, P<.05) was unaffected by CQ (Ang-II+CQ: 61.5%, P=NS vs. Ang-II). Likewise, CQ had no effect on mean maximum suprarenal aortic diameter (Ang-II: 1.91±0.19 mm vs. Ang-II+CQ: 1.97± 0.21 mm, P=NS). Elastin fragmentation, collagen accumulation and smooth muscle attrition were higher in Ang-II treated mice, and remained unaffected by CQ treatment.
Conclusions: Long term CQ administration does not alter the natural history and prognosis of experimental AAA. These data suggest that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms and that manipulating autophagy as a mechanism to reduce AAA may need re-evaluation.
Author Disclosures: A. Ramadan: None. M.D. Wheatcroft: None. A. Quan: None. K.K. Singh: None. F. Lovren: None. H. Teoh: None. M. Al-Omran: None. H. Leong-Poi: None. S. Verma: None.
- © 2014 by American Heart Association, Inc.