Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II-associated aortic remodeling

Abstract

Objective: The pathophysiologic processes of abdominal aortic aneurysms (AAAs) and atherosclerosis often intersect. Given that anomalies in vascular smooth muscle cell (SMC) autophagy have been noted in models of atherosclerosis, we sought to evaluate the potential role that SMC autophagy may play in the initiation and progression of AAAs.

Methods: Studies were conducted in ATG7^flx/flxSM22α-Cre^tg/+ (SMC ATG7 knockout [SMC-ATG7-KO]) and ATG7^WT/WT; SM22α-Cre^tg/+ (SMC ATG7 wild-type [SMC-ATG7-WT]) littermates that were continuously infused with angiotensin II (Ang II; 1.5 mg/kg/d) for up to 12 weeks. Mortality, morbidity, hemodynamics, and aortic remodeling were documented.

Results: During the 12-week observation window, all of the Ang II-treated SMC-ATG-WT mice (n = 6) survived, whereas 10 of the 19 Ang II-treated SMC-ATG-KO mice had died by week 7 (log-rank test, P < .001). Mean arterial pressure (128.07 ± 3.4 mm Hg for Ang II-treated SMC-ATG-KO vs 138.5 ± 5.87 mm Hg for Ang II-treated SMC-ATG-WT mice) and diastolic arterial pressure (109.7 ± 2.55 mm Hg for Ang II-treated SMC-ATG7-KO vs 119.4 ± 2.12 mm Hg for Ang II-treated SMC-ATG7-WT mice) were significantly different between the two groups (P < .01). Cardiac rupture, myocardial infarct, end-organ damage, pleural effusion, and venous distention were noted in Ang II-treated SMC-ATG7-KO but not in Ang II-treated SMC-ATG7-WT mice. Although the suprarenal aortic diameters of the Ang II-treated SMC-ATG7-KO group demonstrated a trending increase (at week 4, 1.26 ± 0.06 mm [n = 14] for Ang II-treated SMC-ATG-KO mice vs 1.09 ± 0.02 mm [n = 5] for Ang II-treated SMC-ATG-WT mice; P < .05), only 2 of the 19 developed abdominal aortic dissections.

Conclusions: Mice with SMC ATG7 deficiency that are chronically infused with Ang II do not tend to develop dissecting AAA but do exhibit adverse aortic remodeling and appreciable cardiac failure-associated mortality.