Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure and premature death. Owing to the poor understanding of the underlying mechanisms of obliterative vascular remodeling, current therapies result in only modest improvement in morbidity and mortality. Bi-allelic mutations of the EIF2AK4 gene [encoding General control nonderepressible 2 (GCN2)] are linked to heritable pulmonary veno-occlusive (PVOD) disease. However, the mechanistic role of GCN2 in regulating pulmonary vascular remodeling and the pathogenesis of PAH has not been reported. Our new Supporting Data show that mice with genetic loss of GCN2 (GCN2-/-) did not spontaneously develop PAH or PVOD under normoxia condition. Surprisingly, GCN2-/- mice were protected from Sugen5416/hypoxia-induced PAH, as evident by reduced right ventricular systolic pressure and pulmonary vascular remodeling. Whole transcriptome RNA-sequencing analysis demonstrated that GCN2 deletion normalized expression of molecules related to cell proliferation including FoxM1 in mouse lungs. GCN2 deficiency inhibits PDGF-BB-induced FOXM1 expression and cell proliferation in cultured human pulmonary arterial smooth muscle cells (hPASMCs). Forced expression of FoxM1 rescued cell proliferation in GCN2-deficient hPASMCs. Thus, we hypothesize that GCN2 regulates vascular remodeling through FoxM1 in the pathogenesis of PAH. Studies in Specific Aim 1 will define the role of GCN2 in the pathogenesis of PAH. Studies in Aim 2 will delineate the mechanism of GCN2-regulated pulmonary vascular remodeling. We will address the hypothesis that GCN2 activation via GCN2/ATF4/FoxM1 signaling is essential for the development of pulmonary vascular remodeling and PAH. Successful completion of the proposed studies will elucidate the potential molecular basis of GCN2/ATF4/FoxM1 signaling pathway in pulmonary vascular remodeling, and provide novel druggable target leading to novel therapeutic strategy for effective treatment of PAH.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|