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. 2023 May 25;8:218. doi: 10.1038/s41392-023-01496-3

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — Activation of IH-associated signaling pathways. IH causes an increase in intracellular ROS, which can activate PLC-γ to produce IP3 and DAG. These two messengers are involved in intracellular signal transduction pathways and induce HIF-1α protein expression and transcriptional activity, respectively. Pathway ① indicates that IH-induced transactivation of HIF-1α requires ROS-mediated phosphorylation of the CaMKII-dependent coactivator p300. Pathway ② indicates that hypoxia-induced HIF-1α protein expression is caused by increased synthesis of mTOR, which is dependent on the ROS/Ca²⁺ signaling pathway. However, the mechanism by which PKC inhibits the reduction in PHD and the mechanism of the PI3K/AKT signaling pathway needs to be further confirmed (③④). Pathway ⑤ indicates that calcium-activated calpain promoted the degradation of HIF-2α protein in arterial corpuscles, resulting in a decrease in SOD2 and impaired antioxidant capacity of cells. Pathway ⑥ indicates that CaMKII can activate IEG genes, increase the transcription of c-fox mRNA or c-jun mRNA and increase the expression of AP-1, which is related to the activation of the sympathetic system and systemic inflammation. Pathway ⑦ indicates that increased ROS could stimulate the increased expression of ET and ETA and induce LTF in the carotid body. Pathway ⑧ indicates that IH causes ROS-dependent inhibition of CO production by HO-2, resulting in a decrease in PKG activity and an increase in H2S produced by CSE, which triggers a chemosensory reflex of the carotid body, leading to sympathetic excitation and hypertension. In addition, elevated H2S could activate the CA_V3.2 T calcium channel on the cell membrane, causing Ca²⁺ influx and further aggravating the damage caused by IH (⑨). IH intermittent hypoxia, PLC-γ phospholipase C γ, PIP2 phosphatidylinositol (4,5) bisphosphate, IP3 inositol-3-phosphate, CaMKII calmodulin-dependent kinase II, IEGs immediate early genes, AP-1 activator protein-1, SOD2 superoxide dismutase 2, ET-1 endothelin 1, ETA endothelin receptor, HO-2 heme oxygenase-2, CO carbon monoxide, PKG: protein kinase G, CSE cystathionine γ-lyase, H2S hydrogen sulfide, LTF long-term facilitation