Abstract 18082: Perk Inhibition Improves Pulmonary Arterial Hypertension in Mice
Introduction: Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling, characterized by endothelial dysfunction and pulmonary artery smooth muscle cell (PASMC) proliferation. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of PAH; however, the mechanism remains to be clarified.
Hypothesis: The PKR- like kinase (PERK), one of the three ER transmembrane stress kinases, plays a pivotal role to the pathogenesis of PAH.
Methods: We employed genetic and pharmacologic approaches to assess the role of PERK in vivo and in vitro. Cultured PASMCs isolated from mice were exposed to hypoxia (O2 4%, 48hrs) in the presence or absence of a PERK inhibitor (PERKI: GSK2606414, 1μM). C57BL/6 mice were exposed to chronic hypoxia (O2 8.5%, 4wks) with intraperitoneal injection of the VEGF receptor-2 inhibitor, SU5416 (20mg/kg/week), and the effect of PERK inhibitor (GSK2606414, 4 mg/kg/day, i.p.) was assessed. Mice with smooth muscle specific deletion of PERK (SMC-PERK KO) were generated and exposed to 4wk hypoxia + SU5416.
Results: In cultured PASMCs, hypoxia induced phosphorylation of PERK, c-myc expression and cellular proliferation, which was inhibited by PERKI. In mice, PERKI significantly attenuated chronic hypoxia+SU5416-induced right ventricular (RV) systolic pressure rise (PERKI 47.3±3.2 vs vehicle 64.8±5.4mmHg ), improved right heart function assessed by RV fractional area change (PERKI 48.7±2.6 vs vehicle 34.6±2.3%), and ameliorated pulmonary vascular remodeling. This was associated with reduced c-myc expression and increased cleaved caspase3 in pulmonary arteries. SMC-PERK KO developed blunted RV systolic pressure rise to chronic hypoxia+SU5416 (KO 43.5±5.5 vs WT 64.5±1.8 mmHg), ameliorated RV dysfunction (KO 53.0±2.7 vs WT 32.5±2.5%) and pulmonary vascular remodeling.
Conclusions: PERK in smooth muscle cells critically contributes to the pathogenesis of PAH in mice. PERKI might be a novel therapeutic strategy to treat pulmonary artery hypertension.
Author Disclosures: T. Shimizu: None. E. Takimoto: None. T. Sumida: None. A.T. Naito: None. I. Komuro: None.
- © 2016 by American Heart Association, Inc.