Endothelial PHD2 deficiency induces nitrative stressviasuppression of caveolin-1 in pulmonary hypertension

Abstract

Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model [Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 (PHD2)] with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) or endothelial Nos3 knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/gRNA plasmid DNA inhibited obliterative pulmonary vascular remodeling and attenuated severe PH in Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PH and improved right heart function. These data suggest that suppression of Caveolin-1 expression secondary to PHD2 deficiency augments nitrative stress through eNOS activation, which contributes to obliterative vascular remodeling and severe PH. Thus, reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension

“…Moreover, E2F1 has been shown to mediate sodium-hydrogen exchanger 1 (NHE1) induced PASMCs proliferation, hypertrophy and migration in vitro (44). E2F1 expression is also significantly increased in the lung of other PH models such as monocrotaline-exposed rats (45) and Egln1 Tie2Cre mice (17,46) (Supplemental Figures 7A and 7B). Overexpression of E2F1 suppressed BMPR2 expression in the HPVECs (Supplemental Figure 7C).…”

E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

“…45 Our studies demonstrated that E2F1 expression and promoter activities are upregulated by SOX17 deficiency in HPVECs likely due to absence of suppression of SOX17 in the proximal region of E2F1 promoter. Moreover, E2F1 has been shown to mediate NHE1 (sodium-hydrogen exchanger 1) induced PASMC proliferation, hypertrophy, and migration 46 E2F1 expression is also significantly increased in the lung of other PH models such as monocrotalineexposed rats 47 and Egln1 Tie2Cre mice 18,48 (Figure S9A and S9B). Overexpression of E2F1 suppressed BMPR2 expression in the HPVECs (Figure S9C).…”

The Role of a Lung Vascular Endothelium Enriched Gene TMEM100

“…These data suggest that TMEM100 deficiency plays an important role in LLDDS pathogenesis. Moreover, our recent study found that TMEM100 is downregulated in a subpopulation of ECs and the whole lung ECs of PH mice ( Egln1 Tie2Cre ), a mouse model with severe PH with progressive obliterative vascular remodeling including vascular occlusion and plexiform-like lesion and right heart failure [ 7 , 23 , 24 ]. Tmem100 was also downregulated in the lungs of mice with PH induced by the overexpression of dominant-negative Bmpr2 [ 25 ].…”

“…Compared to other organs, the lung is of particular interest due to its unique morphological composition, consisting of a thin layer of capillary ECs that enable efficient gas exchange [ 6 ]. Our lab’s long-term research interest is on lung vascular biology and pulmonary vascular diseases [ 7 , 8 ]. Recent findings and publications have uncovered a previously unknown transmembrane protein 100 (TMEM100) that is enriched in lung ECs.…”