Abstract 20684: Reticulon-4 is a Potential Biomarker in Pulmonary Arterial Hypertension (PAH) and May Have a Critical Role in its Pathogenesis
In pulmonary arterial hypertension (PAH) a number of diverse etiologies (BMPR2 mutations, hypoxia, viruses) result in remarkably similar pathology. All of these are associated with variable levels of endoplasmic reticulum (ER) stress. Reticulon-4 (a.k.a Nogo) is involved in regulating ER shape and may function as a pro-survival factor during ER stress. We hypothesized that induced Nogo maybe a biomarker that is also involved in the pathogenesis of PAH. We measured serum Nogo-B levels (ELISA) in PAH (n=41) compared to healthy (n=18) and thromboembolic pulmonary hypertension patients (n=6). PAH patients had a significant increase in serum Nogo-B compared to the other 2 groups (p<0.001). In 7 patients we secured lung tissue (transplant) and found increased Nogo-B expression in resistant pulmonary arteries (PA) in PAH versus normal PAs. Nogo-B expression was also increased in primary PA smooth muscle cell (PASMC) cultures from PAH patients (immunoblot/qRT-PCR). Nogo may also have a causal role in PAH, since Nogo-/- mice are resistant to chronic-hypoxia (CH)-induced PAH. CH-Nogo+/− mice develop PAH to a lesser degree than CH-Nogo+/+ exhibiting a gene dose-dependent effect. Important cellular indices of the pro-proliferative and anti-apoptotic diathesis in PAH are increased [Ca++]i and mitochondrial membrane potential, both of which may be explained by disruption of the ER-mitochondria unit. Indeed, the induction of Nogo in PAH was associated with re-shaped PASMC ER and increased distance between the ER and mitochondria (electron microscopy). To address if this caused functional disruption, we used a phospholipid bioassay. Phosphatidyl-serine (PS) is a lipid synthesized in the ER, then transported to the mitochondria and decarboxylated to phophatidyl-ethanolamine (PE); this occurs exclusively on the contact points between the ER and mitochondria. Human PAH PASMCs had a decrease in radioactive PE, suggesting a functional disruption of the ER-mitochondria unit. Thus Nogo may be both a biomarker and directly involved in PAH pathogenesis. Various stimuli could cause ER stress in PASMC, where the induction of Nogo rescues from mitochondria-dependent apoptosis and serves as a survival factor, but may lead to proliferative remodeling and PAH.
- © 2010 by American Heart Association, Inc.