Dual Roles of Reactive Oxygen Species in Exacerbated Proinflammatory Effects of Caveolin‐2 Deficiency in Ischemia/Reperfusion and the Anti‐inflammatory Effects of Ethanol Preconditioning

Abstract

Caveolin‐2 (Cav‐2), a member of caveolin protein family, is ubiquitously co‐expressed ubiquitously with caveolin‐1 (Cav‐1) in vascular endothelial cells. Cav‐2 interacts with Cav‐1 to form a hetero‐oligomeric complex within caveolae. In contrast with the extensively studied Cav‐1 including the functional role of Cav‐l expressed in ECs in ischemic injury, much less is known regarding the effects of Cav‐2. We hypothesized that (i) genetic deletion of Cav‐2 (CAV‐2 KO) would promote proinflammatory effects in the absence of I/R in wild‐type (WT) mice; (ii) postischemic inflammation will be exacerbated in CAV‐2 KO mice compared to WT animals; (iii) the proinflammatory effects induced by I/R are due to generation of reactive oxygen species (ROS) in CAV‐2 KO mice; and (iv) ingestion of ethanol at low to moderate levels (EPC) 24 hours prior to ischemia (45 min) followed by reperfusion (60 min) (I/R) will limit postischemic inflammation in CAV‐2 KO mice by a ROS‐dependent mechanism. Intravital fluorescence microscopy was used to visualize leukocyte rolling (LR) and adhesion (LA) in single postcapillary venules of the small intes­tine. Prior to I/R, male CAV‐2 KO mice were treated with EPC, MnTBAP (cell‐permeable SOD mimetic) 1 hour prior to I/R, or MnTBAP 20 minutes prior to EPC, respectively, with postcapillary venular LR and LA quantified during the first hour of reperfusion. Our data shown that LR and LA were markedly elevated in male CAV‐2 KO mice under baseline condition relative to that noted in WT animals. I/R‐induced LR and LA were increased to a greater extent in CAV‐2 KO mice compared to WT animals. These postischemic increases in LR and LA were abolished by treatment with EPC or by exposure to MnTBAP 1 hour prior to I/R. MnTBAP pretreatment 20 minutes prior to EPC also abolished the protective effects of EPC. These results indicate that genetic deletion of CAV‐2 produces proinflammatory effects under baseline conditions and exacerbates these effects after I/R by a ROS‐dependent mechanism. Antecedent EPC prevents the proinflammatory responses to I/R in CAV‐2 KO mice. This protective effect of EPC was initiated by ROS.Support or Funding InformationNIH: R01‐AA022108, R01‐HL081860; DOD: W81XWH‐15‐1‐0624.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.