Protective Effects of Dexmedetomidine on the Vascular Endothelial Barrier Function by Inhibiting Mitochondrial Fission via ER/Mitochondria Contact

Abstract

The damage of vascular endothelial barrier function induced by sepsis is critical in causing multiple organ dysfunctions. Previous studies showed that dexmedetomidine (Dex) played a vital role in protecting organ functions. However, whether Dex participates in protecting vascular leakage of sepsis and the associated underlying mechanism remains unknown yet. We used cecal ligation and puncture induced septic rats and lipopolysaccharide stimulated vascular endothelial cells (VECs) to establish models in vivo and in vitro, then the protective effects of Dex on the vascular endothelial barrier function of sepsis were observed, meanwhile, related mechanisms on regulating mitochondrial fission were further studied. The results showed that Dex could significantly reduce the permeability of pulmonary veins and mesenteric vessels, increase the expression of intercellular junction proteins, enhance the transendothelial electrical resistance and decrease the transmittance of VECs, accordingly protected organ functions and prolonged survival time in septic rats. Besides, the mitochondria of VECs were excessive division after sepsis, while Dex could significantly inhibit the mitochondrial fission and protect mitochondrial function by restoring mitochondrial morphology of VECs. Furthermore, the results showed that ER-MITO contact sites of VECs were notably increased after sepsis. Nevertheless, Dex reduced ER-MITO contact sites by regulating the polymerization of actin via α2 receptors. The results also found that Dex could induce the phosphorylation of the dynamin-related protein 1 through down-regulating extracellular signal-regulated kinase1/2, thus playing a role in the regulation of mitochondrial division. In conclusion, Dex has a protective effect on the vascular endothelial barrier function of septic rats. The mechanism is mainly related to the regulation of Drp1 phosphorylation of VECs, inhibition of mitochondrial division by ER-MITO contacts, and protection of mitochondrial function.

Mitochondrial Dynamics: Pathogenesis and Therapeutic Targets of Vascular Diseases

“…In spite of the development of pharmacological agents that target fusion and fission for the prevention and treatment of vascular diseases, several obstacles remain to be solved to achieve this goal ( 87 , 103 , 104 ). First, the therapeutic agent needs to have specificity to target the organ and ascertain the duration time ( 134 ).…”

“…DRP1-mediated mitochondrial fission exerts a critical function in the acute constriction of the ductus arteriosus to O 2 and participates in the subsequent anatomic closure of the ductus arteriosus ( 102 ). Mitochondrial fission also seems indispensable for angiogenesis in ECs ( 103 ). The loss of protein disulfide isomerase active 1 in ECs induces mitochondrial fragmentation and mitochondrial ROS elevation by increasing Cys644 sulfenylation and DRP1 activity, which impair endothelium-dependent vasorelaxation and angiogenesis ( 104 ).…”

Protective Effects of Dexmedetomidine on Sepsis-Induced Vascular Leakage by Alleviating Ferroptosis via Regulating Metabolic Reprogramming

“…The passage 3–5 endothelial cells were used for the follow-up study. 17 LPS (1μg/mL) or Erastin (5µM) were used to incubate VECs for 12 hours to induce an in vitro vascular endothelial injury model. 8 In order to explore the effects of Dex on ferroptosis, VECs were treated with 0.1µM Dex after LPS or Erastin stimulation.…”

“…Then, the average fluorescence intensity of intracellular ROS and mitochondrial ROS was calculated by ImageJ. 17 …”

“…Large studies have demonstrated that mitochondrial morphology plays a key role in the determinant of mitochondrial function. 15 , 16 Our previous study 17 found that the mitochondria of VECs were excessively fissioned in sepsis, and that mitochondrial morphology presented fragmentation, leading to mitochondrial dysfunction. ∆Ψm and ATP levels significantly reduced, and the generation of ROS increased.…”