Fig. 4

The role of 4-OHE in pulmonary hypertension; 4-OHEs competitively decrease the activity of 2-OHE2, inhibiting the formation of 2-ME2. They activate ERs, leading to the production of free radicals and generation of ortho-quinones, resulting in ROS production and DNA damage, which can cause dysfunction of PAECs and promote the proliferation and migration of PASMCs. By binding to ARs, 4-OHEs increase VEGF expression and activate ERK1/2, JNK, and p38MAPK pathways and promote the proliferation of AECs; 4-OHEs induce DDR and upregulate the levels of proinflammatory cytokines IL-1β, IL-6, and TNF, potentially aggravating the deterioration of PH. However, 4-OHEs also increase HO-1 levels through the Nrf2–Keap1–ARE pathway, inhibiting oxidative stress and PASMCs proliferation and promoting apoptosis. In lung tissue, they enhance Nrf2 expression, reducing the levels of proinflammatory cytokines IL-8 and TNF. In LPS-stimulated macrophages, 4-OHEs upregulate GSTP1, decreasing the levels proinflammatory cytokines TNF, NO, iNOS, and COX-2, mitigating inflammation, and potentially ameliorating PH deterioration. Furthermore, they inhibit the PI3K–Akt–mTOR pathway and LC3-II levels, decrease p62 levels, and enhance autophagy stability. 4-OHEs, 4-hydroxyestrogens; 2-OHE2, 2-hydroxyestradiol; 2-ME2, 2-methoxyestradiol; ERs, estrogen receptors; ARs, adrenergic receptors; VEGF, vascular endothelial-derived growth factor; ERK1/2, extracellular signal-regulated kinases1/2; JNK, c-Jun N-terminal kinase; p38MAPK, p38 mitogen-activated protein kinase; AECs, arterial endothelial cells; DDR, DNA damage response; IL, interleukin; TNF, tumor necrosis factor; HO-1, heme oxygenase 1; Nrf2, nuclear factor E2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; ARE, antioxidant response element; LPS, lipopolysaccharide; COX-2, cyclooxygenase-2; GSTP1, glutathione S-transferase P1; NO, nitric oxide; iNOS, inducible nitric oxide synthase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mechanistic target of rapamycin; LC3-II, light chain 3-II