The mechanism of NRF2 regulating cell proliferation and mesenchymal transformation in pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disease with no existing curative drugs. NF-E2-related factor 2 (NRF2) a pivotal molecular in cellular protection, was investigated in PH models to elucidate its role in regulating abnormal phenotypes in pulmonary artery cells. We examined the expression of NRF2 in PH models and explored the role of NRF2 in regulating abnormal phenotypes in pulmonary artery cells. We determined the expression level of NRF2 in lung tissues of PH model decreased significantly. We found that NRF2 was reduced in rat pulmonary artery endothelial cells (rPAEC) under hypoxia, while it was overexpressed in rat pulmonary artery smooth muscle cells (rPASMC) under hypoxia. Next, the results showed that knockdown NRF2 in rPAEC promoted endothelial-mesenchymal transformation and upregulated reactive oxygen species level. After the rPASMC was treated with siRNA or activator, we found that NRF2 could accelerate cell migration by affecting MMP2/3/7, and promote cell proliferation by regulating PDGFR/ERK1/2 and mTOR/P70S6K pathways. Therefore, the study has shown that the clinical application of NRF2 activator in the treatment of pulmonary hypertension may cause side effects of promoting the proliferation and migration of rPASMC. Attention should be paid to the combination of NRF2 activators.

Inhibition of IP3R3 attenuates endothelial to mesenchymal transition induced by TGF-ß1 through restoring mitochondrial function.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure and right ventricular hypertrophy. Inositol 1,4,5-trisphosphate receptors (IP3Rs) release calcium ions from the endoplasmic reticulum to regulate permeability and migration of endothelial, thereby affecting PAH. In this study, We determined the expression level of IP3R3 and its position in lung tissue from PAH rat models, and stud the effect of IP3R3 on endothelial to mesenchymal transition (EndMT) and mitochondrial function of endothelial cells treated with TGF-ß1. We observed that IP3R3 was significantly overexpressed in the lung tissues from PAH rat models. Inhibition of IP3R3 reduced EndMT markers, cell migration, ROS production, Ca2+ levels, increased mitochondrial membrane potential and mitochondrial respiratory chain complex I, III, and V activities. These results suggest that the inhibition of IP3R3 attenuated EndMT and migration induced by TGF-ß1 via restoring of mitochondrial functions, thereby suggesting a novel therapeutic opportunity for PAH.