Abstract 19343: Chemical Chaperone Mediated Inhibition of Activating Transcription Factor 6 (ATF6) is a Novel Therapy in Pulmonary Arterial Hypertension (PAH)

Abstract

The high mortality associated with PAH is in part, due to the poorly understood pathogenesis. Endoplasmic reticulum (ER)-stress is a potential commonality among many molecular triggers of PAH, including mutations, viruses, inflammation and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing for exchange of Ca2+. Recently, we showed that ER-mito unit disruption was critical in PAH pathogenesis. In pulmonary artery smooth muscle cells (PASMCs), ER-stress activated the transcription factor ATF6, increased levels of the ER protein Nogo, disrupted the ER-mito unit, and resulted in the apoptosis-resistance that is central to pulmonary vascular remodeling in PAH. Chemical chaperones including the FDA-approved 4-phenylbutyrate (PBA) attenuate ER-stress and have been studied in metabolic diseases and cancer. We hypothesized that attenuation of ER stress-induced ATF6 activation with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. Hypoxic mice or monocrotaline-injected rats were treated with PBA in their drinking water (~500mg/kg/day) in prevention (days 0-28) and reversal (days 14-28) protocols. Mechanistic studies were performed in lungs and PASMCs exposed to hypoxia. PBA decreases ATF6 activation (nuclear localization, luciferase, target gene (Nogo/GRP78) expression) and normalizes mitochondrial function (mitochondrial-Ca2+, membrane potential, reactive oxygen species). Both in vivo and in vitro, PBA suppresses proliferation (Ki67) and induces apoptosis (TUNEL). Treated mice had less pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity compared to vehicle-treated controls (see table; data presented as mean±SEM). Treated rats responded similarly. Chemical chaperones improve PAH by inhibiting ATF6 activation, a pathway compatible with several PAH-triggers that induce ER-stress.