Abstract 38: Endoplasmic Reticulum Stress Pathway-mediated Apoptosis is Involved in Ang II Induced Abdominal Aortic Aneurysm

Abstract

Backgroud— Abdominal aortic aneurysms (AAA) represent a unique and dramatic example of vessel wall remodeling characterized by degeneration of the elastic media. Apoptosis of vascular smooth muscle cells plays an important role in the pathogenesis of AAA. However, the potential mechanism remains poorly understood. Endoplasmic reticulum stress (ER stress)-induced apoptosis has been proved to be one of the important pathogenesis of cardiovascular disease. However, whether ER stress is involved in AAA is still not known. We assessed the hypothesis that ER-associated apoptosis is involved in Angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient mice. Methods and Results— Mice were infused with Ang II (1000 ng/kg per minute) with or without ER stress inhibitor (taurine-conjugated ursodeoxycholic acid) for 4 weeks. Mice infused with Ang II displayed an increase in aortic diameter. Detection of apoptosis was performed with the TUNEL assay. We performed Western blot and Real-time PCR to analyze indicators of ER molecule chaperone and ER-associated apoptosis. Glucose Regulated Proteins 78 and 94 (GRP78/BiP and GRP94), the ER chaperone, were up-regulated significantly in AAA compared to control. Furthermore, the hallmarks of ER-associated apoptosis, C/EBP homologous protein (CHOP), caspase-12 and PERK-eIF2-ATF4 signaling pathway were found to have activated in the AAA. The inhibition of ER stress significantly decreased maximal aortic diameter by 31% and abdominal aortic weight by 35% ( P <0.05, respectively). ER stress inhibitor also reduced GRP 78, CHOP and caspase-12 expression ( P <0.05, respectively). Taken together, these results suggested that apoptosis induced by ER stress may contribute to the development of AAA. Conclusions— ER stress response is involved in the pathogenesis of Ang II induced AAA in apolipoprotein E-deficient mice. ER stress inhibition attenuates AAA formation during Ang II infusion in apolipoprotein E-deficient mice. Therefore, ER stress could be a potential target for AAA.