Renal microvascular endothelial cells (RMECs), which are closely related to regulation of vascular reactivity and modulation of inflammation, play a crucial role in the process of renal ischemia and reperfusion (I/R) injury. Previous studies have reported the protective effects of dexmedetomidine (DEX) against renal I/R injury, but little is known about the role of DEX on RMECs. This study aimed to investigate whether DEX alleviated renal I/R injury via acting on the RMECs. Mice underwent bilateral renal artery clamping for 45 min followed by reperfusion for 48 h, and the cultured neonatal mice RMECs were subjected to hypoxia for 1 h followed by reoxygenation (H/R) for 24 h. The results suggest that DEX alleviated renal I/R injury in vivo and improved cell viability of RMECs during H/R injury in vitro. Gene sequencing revealed that the PI3K/Akt was the top enriched signaling pathway and the endothelial cells were widely involved in renal I/R injury. DEX activated phosphorylation of PI3K and Akt, increased eNOS expression, and attenuated inflammatory responses. In addition, the results confirmed the distribution of α₂ adrenoreceptor (α₂ -AR) in RMECs. Furthermore, the protective effects of DEX against renal I/R injury were abolished by α₂ -AR antagonist (atipamezole), which was partly reversed by the PI3K agonist (740 Y-P). These findings indicated that DEX protects against renal I/R injury by activating the PI3K/Akt-eNOS pathway and inhibiting inflammation responses via α₂ -AR in RMECs.

Aims

Myocardial injury after noncardiac surgery (MINS) is common in elderly patients and considered as an independent predictor of 30-day mortality after noncardiac surgery. Dexmedetomidine possesses cardiac-protective profile. Previous clinical studies have found that perioperative application of dexmedetomidine is associated with decreased 1-year mortality in patients undergoing cardiac surgery. The current study protocol aims to investigate the effects of dexmedetomidine on the incidence of MINS, complications, and 30-day mortality in elderly patients subjected to noncardiac surgery.

Methods

A multicenter, randomized, controlled, double-blind, prospective trial is designed to explore cardiac protection of dexmedetomidine in the elderly patients undergoing noncardiac surgery. A total of 960 patients aged over 65 years will be recruited and randomly assigned to dexmedetomidine group (group Dex) and normal saline placebo group (group NS) in a ratio of 1:1. Patients in group Dex will receive a bolus dose of 0.5 μg/kg dexmedetomidine within 10 min before surgical incision, followed by a consistent infusion at the rate of 0.3-0.5 μg/kg/h throughout the operation. Group NS patients will receive the same volume of normal saline. The primary outcome is the incidence of MINS via detecting the hs-TnT level within 3 days after the operation. The secondary outcome includes myocardial ischemic symptoms, the incidence of major adverse cardiovascular events (MACE) in hospital, length of ICU and postoperative hospital stay, the incidence of inhospital complications, and 30-day all-cause mortality.

Discussion

The results of the current study will illustrate the effect of dexmedetomidine on myocardial injury for elderly patients undergoing major noncardiac surgery.

Trial registration

The trial was registered with Chinese Clinical Trial Registry (CHICTR) on Aug 24, 2021 (ChiCTR2100049946, http://www.chictr.org.cn/showproj.aspx?proj=131804 ).

Lipid metabolism has been considered as a potential therapeutic target in sevoflurane-induced neurotoxicity that can potentially affect the learning and memory function in the developmental brain. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) is identified as a crucial step in regulating lipid metabolism and associated with the pathogenesis of neurodegenerative diseases. Herein, it is reported that quercetin modified Cu_{2- x} Se (abbreviated as CSPQ) nanoparticles can ameliorate sevoflurane-induced neurotoxicity by tuning the microglial lipid metabolism and promoting microglial M2-like polarization via TREM2 signaling pathway, in which the apolipoprotein E (ApoE), and adenosine triphosphate-binding cassette transporters (ABCA1 and ABCG1) levels are upregulated. Furthermore, the protective effects of CSPQ nanoparticles against sevoflurane-induced neurotoxicity via TREM2 are further demonstrated by the small interfering RNA (siRNA)-TREM2 transfected BV2 cells, which are obviously not influenced by CSPQ nanoparticles. The cell membrane coated CSPQ (referred as CSPQ@CM) nanoparticles can significantly reduce sevoflurane-induced learning and memory deficits, improve lipid metabolism dysfunction, and promote the remyelination in the hippocampus of mice. The study shows great potential of targeting microglial lipid metabolism in promoting remyelination of neurons for treatment of neurotoxicity and neurodegenerative diseases.