Abstract 17: Prolonged ER Stress Induced by Angiotensin II-Hypertension Contributes to Aortic Stiffening via an Increase in Pro-apoptotic and Pro-inflammatory Signaling Pathways

Abstract

Aortic stiffening is an important predictor of negative cardiovascular outcomes and is associated with hypertension. Angiotensin II (Ang II) is a mediator of aortic stiffening via upregulation of pro-inflammatory and pro-apoptotic signaling pathways, however the mechanisms mediating this upregulation are unclear. Endoplasmic reticulum (ER) stress occurs during cardiovascular diseases, leads to upregulation of pro-inflammatory and pro-apoptotic pathways and can be induced by Ang II. We hypothesized that ER stress leads to vascular apoptosis and inflammation contributing to increased aortic stiffening during Ang II-induced hypertension. Twelve-week old Sprague-Dawley rats were implanted with mini-osmotic pumps containing Ang II (60ng/min/day, 28 days) or received sham surgery and co-treated with ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) or 4-phenylbutyric acid (PBA) (100mg/kg/day, i.p. 28 days) or saline. Thoracic aorta was used for functional myograph analysis and western blot (data presented as fold change from control ± SEM). Aortic rings from the Ang II saline group had a greater contraction to phenylephrine compared to control (Emax: 33.1±0.7 mN vs 26.8±0.6 mN) which was attenuated by ER stress inhibition (Emax: 23.4±0.4 mN,PBA; 26.05±0.7 mN,TUDCA). ER stress inhibition suppressed NF-κB phosphorylation (1.0±0.4, PBA; 1.3±0.2, TUDCA) compared to Ang II saline group (1.9± 0.4). ER stress inhibition reduced pro-apoptotic protein Bax expression (1.3± 0.7, PBA; 1.8± 0.1, TUDCA) compared to Ang II saline group (2.5±0.7) and increased anti-apoptotic protein Bcl-2 expression (1.2±0.5, PBA; 1.3±0.4, TUDCA) compared to Ang II saline group (0.6 ±0.2). Collagen type I and type III expression was attenuated with ER stress inhibition (1.5±0.2, PBA; 1.4±0.4, TUDCA and 1.0±0.3, PBA; 0.9±0.4 TUDCA, respectively) compared to Ang II saline group (3.7±0.4 and 1.8±0.3, respectively). These effects were independent of blood pressure changes as ER stress inhibition did not alter systolic blood pressure (163±3 mmHg, PBA; 170±4 mmHg, TUDCA) compared to Ang II saline group (165±4 mmHg). Our data suggest that ER stress is a new mechanism through which Ang II promotes vascular inflammation and apoptosis resulting in increased aortic stiffness.