Abstract TMP116: Pharmacological Inhibition Of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysm Rupture

Abstract

Background: The endoplasmic reticulum (ER) is responsible for cellular protein synthesis and folding. Cellular stimuli that perturb ER homeostasis create an imbalance between the protein-folding load and capacity of ER, causing unfolded or misfolded proteins to accumulate in the ER lumen, known as ER stress. Recent studies suggested that ER stress plays significant roles in the pathogenesis of inflammatory vascular diseases. Since inflammation is emerging as a vital component of the pathophysiology of intracranial aneurysms, we hypothesized that ER stress promotes the development of aneurysm rupture by inducing sustained vascular wall inflammation. We tested this hypothesis utilizing pharmacological approaches in mice. Methods: We used 10-week-old male C57BL/6J mice and induced intracranial aneurysms by combining an elastase injection and hypertension. We tested the effects of an ER stress activator (Tunicamycin) and inhibitor (4-phenylbutyric acid, 4-PBA) on the development of aneurysmal rupture. In addition, we assessed the roles of ER stress induced via deactivation of epidermal growth factor receptor (EGFR) by Erlotinib on aneurysm rupture. Results: The pharmacological inhibition of ER stress significantly decreased the rupture rate (P<0.05, Fig. A). Meanwhile, there was a trend for the ER stress activator to increase the rupture rate (P=0.17, Fig.B). Moreover, the pharmacological inhibition of the EGFR pathway with Erlotinib significantly reduced the rupture rate (P<0.05, Fig. C). In addition, Erlotinib treatment reduced the mRNA expression of ER stress markers GRP78 and CHOP (Fig.D-E). Conclusions: The pharmacological inhibition of ER stress decreased aneurysmal rupture in a mouse model of intracranial aneurysm. In addition, inhibition of EGFR decreased aneurysm rupture through the reduction of ER stress. Our findings suggest that ER stress and its upstream EGFR pathway may serve as novel therapeutic targets for preventing aneurysm rupture.