Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1

Abstract

Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2 deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2 deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2 deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.

Age- and Sex-Dependent Caveolar Gene Expression in Normoxic and Post-Ischemic Mouse Hearts

“…In an aging model of the mouse brain, Cav2 transcript & protein was found to be up-regulated which was associated with age-related neuroinflammation (Park et al, 2022). In contrast, a recent study suggested a protective role of Cav2 in an intestinal model of I-R injury where infiltrating cytotoxically activated leukocytes were found in Cav2 -deficient mice subjected to I-R which were associated with enhanced leukocyte rolling, adhesion and injury (Liu et al, 2021). Collectively, suppression of Cav-1, -2 and -3 is predicted to significantly impair the hearts ability to withstand or adapt to ischemic insult with age.…”

“…Cav2 in an intestinal model of I-R injury where infiltrating cytotoxically activated leukocytes were found in Cav2-deficient mice subjected to I-R which were associated with enhanced leukocyte rolling, adhesion and injury (Liu et al, 2021). Collectively, suppression of Cav-1, -2 and -3 is predicted to significantly impair the hearts ability to withstand or adapt to ischemic insult with age.…”

From blood to brain: blood cell-based biomimetic drug delivery systems

“…Leukocytes are guardians of the body and have distinct physicochemical and biological characteristics. Leukocytes are the most widely explored drug delivery systems for their (1) adhesive ability (Liu et al., 2021 ), (2) migration and chemotaxis ability under diseased status (Kameritsch & Renkawitz, 2020 ), and (3) high loading capacity and efficient cargo convey (Huang et al., 2018 ). Leukocytes-based vehicles, for their inherent recruitment property, are especially suitable for drug delivery to brain diseases with inflammation.…”