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PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal
1Anesthesia Surgery Center, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region 830000, China.
Background:
Postoperative cognitive dysfunction (POCD) is a postoperative complication that can be induced by anaesthesia. PCSK9 has been shown to have a role in neuronal development and apoptosis. However, PCSK9 has not been studied in sevoflurane-induced POCD-related disorders.
Objective:
To explore whether PCSK9 can exacerbate sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signalling.
Methods:
A POCD model was constructed by stimulating BV2 microglia with Sevoflurane. CCK8 was used to detect the cell viability, and immunofluorescence was used to observe the expression of microglial activation markers (Iba-1, CD11b) and BDNF to determine the activation of BV2 microglia. Cell proliferation was measured by EDU staining, and apoptosis was analyzed by flow cytometry and western blot. The levels of inflammatory cytokines, ROS, MDA, SOD and CAT were respectively detected by ELISA, DCFH-DA staining, and kits to determine the neuroinflammation and oxidative stress of cells. Mitochondrial ROS, mitochondrial membrane potential, mtDNA and ATP levels were measured to evaluate cellular mitochondrial function.
Results:
Transfection of si-PCSK9 inhibited Sevoflurane-induced microglial activation and restored cellular viability, promoted cell proliferation, inhibited apoptosis and neuroinflammation, decreased ROS and MDA levels in the cells while up-regulating the levels of SOD and CAT, thus inhibiting oxidative stress, restored the mitochondrial membrane potential to normal and decreased mitochondrial ROS and mtDNA levels and increased ATP production, thereby alleviating mitochondrial dysfunction. Moreover, PCSK9 depletion also down-regulated the expression of cGAS and STING to inactivate cGAS-STING signaling. However, cGAS overexpression partially reversed the effects of si-PCSK9.
Conclusion:
PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by upregulating cGAS-STING signaling.
