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O‑GlcNAcylation contributes to intermittent hypoxia‑associated vascular dysfunction via modulation of MAPKs but not CaMKII pathways.

ABSTRACT: Intermittent hypoxia (IH) leads to vascular dysfunction, and O‑linked‑β‑N‑acetylglucosamine (O‑GlcNAc)ylation may regulate vascular reactivity through the modulation of intracellular signaling. The present study hypothesized that O‑GlcNAc modifications contributed to the vascular effects of acute IH (AIH) and chronic IH (CIH) through the MAPK and Ca²⁺/calmodulin‑dependent kinase II (CaMKII) pathways. Rat aortic and mesenteric segments were incubated with DMSO, O‑GlcNAcase (OGA) or O‑GlcNAc transferase (OGT) inhibitor under either normoxic or AIH conditions for 3 h, and arterial function was then assessed. Meanwhile, arteries isolated from control and CIH rats were exposed to 3 h of incubation under normoxic conditions using DMSO, OGA or OGT as an inhibitor, before assessing arterial reactivity. CIH was found to increase the expression of vascular O‑GlcNAc protein and OGT, phosphorylate p38 MAPK and ERK1/2, and decrease OGA levels, but it had no effects on phosphorylated CaMKII levels. OGA inhibition increased global O‑GlcNAcylation and the phosphorylation of p38 MAPK, ERK1/2 and CaMKII, whereas OGT blockade had the opposite effects. OGA inhibition preserved acetylcholine‑induced relaxation in AIH arteries, whereas OGT blockade attenuated the relaxation responses of arteries under normoxic conditions or undergoing AIH treatments. However, the impairment of acetylcholine dilation in CIH mesenteric arteries was improved. CIH artery contraction was increased following angiotensin II (Ang II) exposure. Blockade of p38 MAPK and ERK1/2, but not CaMKII, attenuated Ang II‑induced contractile responses in CIH arteries isolated from the non‑OGT inhibitor‑treated groups. OGT inhibition significantly blocked contractile responses to Ang II and abolished the inhibitory effects of MAPK inhibitors. These findings indicated that O‑GlcNAcylation regulates IH‑induced vascular dysfunction, at least partly by modulating MAPK, but not CaMKII, signaling pathways.

SUBMITTER: Guo X

PROVIDER: S-EPMC8430318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

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O‑GlcNAcylation contributes to intermittent hypoxia‑associated vascular dysfunction via modulation of MAPKs but not CaMKII pathways.

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