Abstract 17076: Attenuating Endoplasmic Reticulum (ER) Stress as a Novel Therapeutic Strategy in Pulmonary Arterial Hypertension

The poor prognosis associated with pulmonary arterial hypertension (PAH) is in part, due to the complex and poorly understood pathogenesis. ER stress is a potential common denominator among many of the seemingly unrelated molecular triggers of PAH, including BMPRII mutations and the misfolded protein response that follows, viruses, inflammation, Notch signaling and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing exchange of Ca2+, lipids and ATP between the organelles. Recently, we showed that disruption of the ER-mito unit was critical in PAH pathogenesis. ER stress-regulated induction of the reticulon protein Nogo caused structural/functional disruption of the ER-mito unit resulting in PAH. Chemical chaperones including the clinically studied 4-phenylbutyrate (PBA) can attenuate ER-stress and have been used in animals and patients to treat metabolic diseases and cancer. We hypothesized that attenuation of ER stress with PBA will prevent the disruption of the ER-...