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Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease.

Authors: Manaud, Grégoire  Nossent, Esther J  Lambert, Mélanie  Ghigna, Maria-Rosa  Boët, Angèle  Vinhas, Maria-Candida  Ranchoux, Benoit  Dumas, Sébastien J  Courboulin, Audrey  Girerd, Barbara  Soubrier, Florent  Bignard, Juliette  Claude, Olivier  Lecerf, Florence  Hautefort, Aurélie  Florio, Monica  Sun, Banghua  Nadaud, Sophie  Verleden, Stijn E  Remy, Séverine  Anegon, Ignacio  Bogaard, Harm Jan  Mercier, Olaf  Fadel, Elie  Simonneau, Gérald  Vonk Noordegraaf, Anton  Grünberg, Katrien  Humbert, Marc  Montani, David  Dorfmüller, Peter  Antigny, Fabrice  Perros, Frédéric 
Citation: Manaud G, etal., Am J Respir Cell Mol Biol. 2020 Jul;63(1):118-131. doi: 10.1165/rcmb.2019-0015OC.
Pubmed: (View Article at PubMed) PMID:32209028
DOI: Full-text: DOI:10.1165/rcmb.2019-0015OC

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4 -/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD.


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CRRD Object Information
CRRD ID: 38549370
Created: 2020-09-01
Species: All species
Last Modified: 2020-09-01
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.