Attenuating Endoplasmic Reticulum Stress as a Novel Therapeutic Strategy in Pulmonary Hypertension
Background—Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries (PA) of patients with pulmonary arterial hypertension (PAH) has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with PAH like hypoxia, inflammation or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of ATF-6, which via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in PAH that promotes proliferation and apoptosis resistance in the PA wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid (TUDCA), will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse PAH.
Methods and Results—PBA in the drinking water both prevented and reversed chronic hypoxia induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, PA remodeling, right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and TUDCA improved ER stress indices in vivo and in vitro, decreased ATF6 activation (cleavage, nuclear localization, luciferase and downstream target expression) and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition these chemical chaperones suppressed proliferation and induced apoptosis in PA smooth muscle cells in vitro and in vivo.
Conclusions—Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
- Received July 31, 2012.
- Accepted November 2, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited