Abstract 18517: GCN2 Dysfunction at the Heart of Pulmonary Veno-Occlusive Disease Development
Background: We identified autosomal recessive bi-allelic mutations in the EIF2AK4 gene (coding for GCN2) as the major genetic cause of pulmonary veno-occlusive disease (PVOD). Recently, we created the first rat model of PVOD induced by mitomycin C (MMC) exposure. Interestingly PVOD was associated with a loss of pulmonary GCN2 content in this model.
Methods and results: We performed a kinetic of PVOD development after MMC exposure (day 0, 7, 14, 21, 28, 35 and 42) at the heart and lung level. Among other, we quantified over time variations in the pulmonary content of proteins involved in proliferation (PCNA, p-P38, p-ERK1/2, p-MET), apoptosis (PARP, cleaved PARP), essential ion channels (KCNK3, TRPC1), inflammation (CD45), endothelial to mesenchymal transition (Twist-1, p120catenin, vimentin), BMPR2 signaling (BMPR-II, BMP4, p-SMAD1/5/8), and GCN2 signaling (GCN2, p-EIF2α, ATF4). We compared this molecular kinetic with heart and lung remodeling related to disease progression. All these crucial mediator of PVOD pathogenesis were significantly altered as compared to control, only in the late time points of the kinetic (at day 28 and further after MMC exposure), when PH become symptomatic (pulmonary vascular occlusion, heart hypertrophy and failure). All except molecules of the GCN2 signaling. Pulmonary GCN2 content was dramatically wasted as soon as 7 days after MMC exposure. We evidenced that contrarily to what one might think, there is no molecular cataclysm after acute MMC intoxication. We demonstrated rather a specific and early loss of GCN2 signaling that can be seen as a trigger of subsequent molecular, morphological and pulmonary vascular functional impairments relevant of PVOD. Interestingly rapamycin treatment was able to restore GCN2 expression and to reduce PH in vivo. Surprisingly, our work also demonstrated that disease evolution in MMC-induced PVOD is primarily characterized by arterial remodeling and only secondary followed by severe venous remodeling.
Conclusions: Our results suggest that loss of pulmonary GCN2 may be an early trigger of pulmonary vascular remodeling in MMC-induced PVOD. Those results may be translated to other forms of PVOD. Our work also highlights the unexpected role of arterial remodeling in PVOD development.
Author Disclosures: F. Antigny: None. E.J. Nossent: None. M. Lambert: None. B. Ranchoux: None. D. Montani: None. B. Girerd: None. F. Soubrier: None. F. Lecerf: None. H.J. Bogaard: None. E. Fadel: None. G. Simonneau: None. A. Vonk Noordegraaf: None. K. Grünberg: None. M. Humbert: None. P. Dorfmüller: None. F. Perros: None.
- © 2016 by American Heart Association, Inc.