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Fig. 2 | Cellular & Molecular Biology Letters

Fig. 2

From: Decoding the enigmatic estrogen paradox in pulmonary hypertension: delving into estrogen metabolites and metabolic enzymes

Fig. 2

The mechanism of 16α-OHE promoting pulmonary hypertension. In PASMCs, 16α-OHE1 binds with ERα to inhibit Nrf2, resulting in upregulation of Nox1 and Nox4, decreased antioxidants increased ROS production, and irreversible PTP oxidation. Activation of the p38MARK pathway leads to increased phosphorylation of CRE region and ATF-2, upregulation of cyclinD1, and promotion of cell oxidative damage and proliferation. Upregulation of miRNA-29 inhibits expression of PPARγ, further reducing CD36 and Glut4 and upregulating PFKP, resulting in insulin resistance and increased aerobic glycolysis of 16α-OHE1, which may promote cell, migration, and antiapoptosis by reducing BMPR2 levels and inhibiting the BMPR2-Smad1/5/8-ID1, BMPR2-AkT-Wnt/β-Catenin, and BMPR2-PPARγ-apoe signaling pathways through lysosomal activation. In PAECs, 16α-OHE1 binds with Erα to inhibit X17, upregulate HIF-2α, and increases cyclin D2 and E2F1, promoting cell proliferation. Additionally, 16α-OHE1 inhibits PPARγ and attenuates mitochondrial bioenergy and insulin resistance, leading to metabolic abnormalities. Inhibition of PPARγ and BMPR2 promotes EndoMT through inhibition of p-Smad1/5/8-Smad4 signaling and enhancement of TGF-β-Smad2/3-Smad4 signaling. E3 stimulates the expression of TNF and IL-6, potentially exerting a proinflammatory effect in PH. E3, estriol; 16α-OHE1/2, 16α-hydroxyestrone/16α-hydroxyestradiol; TNF, tumor necrosis factor; IL-6, interleukin-6; Nrf2, nuclear factor E2-related factor 2; SOD1, superoxide dismutase 1; ROS, reactive oxygen species; Nox1/4, nicotinamide adenine dinucleotide phosphate oxidase1/4; PTP, protein tyrosine phosphatases; p38MARK, p38 mitogen-activated protein kinase; CRE, cAMP response element; ATF-2, activating transcription factor 2; ERs, estrogen receptors; SOX17, SRY-related HMG-box 17; HIF-2α, hypoxia-inducible factor 2α; E2F1, E2F transcription factor 1; PPARγ, peroxisome proliferator-activated receptor γ; CD36, cluster of differentiation 36; Glut4, glucose transporters type 4; PFKP, platelet-type phosphofructokinase; BMPR2, bone morphogenetic protein receptor type II; Id1, DNA binding 1; Akt, protein kinase B; apoE, apolipoprotein E; TGF-β, transforming growth factor-β; EndoMT, endothelial-to-mesenchymal transition; PASMC, pulmonary artery smooth muscle cell; PAEC, pulmonary arterial endothelial cell

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