GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease

Abstract

Pulmonary veno-occlusive disease (PVOD) is a fatal disease of pulmonary vascular lesions leading to right heart failure. Heritable PVOD (hPVOD) is related to biallelic mutation of EIF2AK4 (encoding GCN2), but its molecular mechanism remains unclear. In this study, we aimed to investigate the pathogenesis of PVOD and to find potential drug targets for PVOD. GCN2 dysfunction led to an enhanced transcription of collagen I gene ( col1a1 and col1a2) through decreasing ATF3-dependent p38 phosphorylation inhibition in PVOD, which promotes the collagen I synthesis in pulmonary arterial smooth muscle cells (PASMCs) and eventually leads to increased collagen deposition in pulmonary artery. Four GCN2 knockout (KO) cell lines (exon 15 or 33 mutation) were successfully constructed by epiCRISPR system. Two induced pluripotent stem cells (iPSCs) were generated by reprogramming peripheral blood mononuclear cells (PBMCs) of PVOD patient. It was also comfirmed that GCN2 dysfunction could lead to increased expression of collagen I in lateral plate mesoderm lineage-smooth muscle cells (LM-SMCs) differentiated from both GCN2 KO cell lines and iPSCs. SB203580 (a specific inhibitor of p38) improved hemodynamics and pulmonary vascular remodeling in mitomycin C (MMC)-induced PVOD rats by right ventricle echocardiography. On the whole, we proposed that GCN2 deficiency decreased ATF3-dependent p38 phosphorylation inhibition in PVOD development and suggested a potential therapeutic reagent of SB203580 for the treatment of the disease.

Reviewing the Regulators of COL1A1

“…The TGFβ-induced downstream pathways vary with a consensus on the involvement of p42/p44 Mitogen-Activated Protein Kinase (MAPK). Increased phosphorylation of p38 was associated with increased COL1A1 mRNA levels, in in vitro systems related to pulmonary veno-occlusive disease [ 58 ] and liver fibrosis [ 59 ]. The downstream interactors of p38 affecting COL1A1 mRNA expression were, however, not described [ 58 , 59 ].…”

The EIF2AK4/rs4594236 AG/GG Genotype Is a Hazard Factor of Immunoglobulin Therapy Resistance in Southern Chinese Kawasaki Disease Patients

“…Several studies demonstrated that EIF2AK4 was associated with vascular remodeling ( Lu et al, 2014 ; Nossent et al, 2018 ; Chen et al, 2021 ). One possible mechanism was that EIF2AK4 dysfunction enhanced collagen I gene transcription via the ATF3/p38 pathway, which led to increased collagen deposition in the pulmonary artery ( Chen et al, 2021 ).…”

“…Several studies demonstrated that EIF2AK4 was associated with vascular remodeling ( Lu et al, 2014 ; Nossent et al, 2018 ; Chen et al, 2021 ). One possible mechanism was that EIF2AK4 dysfunction enhanced collagen I gene transcription via the ATF3/p38 pathway, which led to increased collagen deposition in the pulmonary artery ( Chen et al, 2021 ). As vascular remodeling is critical for CAL formation of KD, we also investigated the association between EIF2AK4 /rs4594236 polymorphism and CAL or CAA formation of KD.…”

Differential Expression Profile of microRNAs and Tight Junction in the Lung Tissues of Rat With Mitomycin-C-Induced Pulmonary Veno-Occlusive Disease

“…Studies have shown that the mutation of GCN2 is linked to the development of PVOD and the expression of GCN2 is significantly decreased in patients with PVOD and MMC-induced rat pulmonary microvascular endothelial cells ( 20 – 22 ). In addition, Chen et al ( 23 ) found that GCN2 deficiency decreased ATF3-dependent p38 phosphorylation inhibition in development of PVOD. This implies that GCN2 plays an important role in the pathogenesis of PVOD.…”