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Empagliflozin mitigates endothelial inflammation and attenuates endoplasmic reticulum stress signaling caused by sustained glycocalyx disruption.

ABSTRACT: The disruption of the endothelial cell (EC) glycocalyx (GCX) leads to cellular dysfunction promoting inflammation and cardiovascular disease progression. Recent studies have shown that empagliflozin (EMPA; Jardiance), a sodium-glucose cotransporter 2 inhibitor used in the treatment of type 2 diabetes, can improve EC functions impacted by GCX disruption although the exact cellular mechanisms remain to be elucidated. In this study, the effect of EMPA on EC inflammatory response induced by sustained GCX disruption was investigated. Human aortic ECs were cultured under shear (10 dyne/cm²) for 24 h with or without sustained degradation of heparan sulfate (HS). HS degradation increased inflammatory cell adhesion to ECs. EMPA (50 μM) normalized adhesion levels under sustained HS degradation. Protein expressions of eNOS, phospho-eNOS Ser1177 and ICAM-1 remained unchanged between conditions. Transcriptome analysis revealed the induction of the unfolded protein response (UPR) through the increased expression of ATF3, ATF4, DDIT3 (CHOP), EIF2AK3 (PERK), HSPA5 (Grp78), PPP1R15A (GADD34) and TRIB3 which was in part downregulated by EMPA. mRNA and protein expression of thioredoxin interacting protein (TXNIP) was also downregulated by EMPA. Mitigation of oxidative stress with N-Acetyl-L-cysteine resulted in similar reduction in inflammatory cell adhesion compared to EMPA which could indicate a potential mechanism by which EMPA normalized the inflammatory response. In conclusion, this study demonstrated the potential of EMPA to resolve the inflammatory response of ECs caused by sustained GCX disruption while altering UPR signaling under endoplasmic reticulum stress.

SUBMITTER: Campeau MA

PROVIDER: S-EPMC9314417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe endothelial glycocalyx (EG) on the luminal surface of endothelial cells contributes to the permeability barrier of vessels and prevents activation of the coagulation cascade. Endothelial glycocalyx damage, which occurs in the shock state, results in endotheliopathy. Interleukin (IL)-22 is a cytokine with both proinflammatory and anti-inflammatory properties, and how IL-22 affects the EG has not been studied. We hypothesized that IL-22:Fc, a recombinant fusion protein with human IL-22 and the Fc portion of human immunoglobulin G1 (which extends the protein half-life), would not affect EG shedding in endothelium after injury.MethodsHuman umbilical vein endothelial cells (HUVECs) were exposed to 1 μg/mL lipopolysaccharide (LPS). Lipopolysaccharide-injured cells (n = 284) were compared with HUVECs with LPS injury plus 0.375 μg/mL of IL-22:Fc treatment (n = 293) for 12 hours. These two cohorts were compared with control HUVECs (n = 286) and HUVECs exposed to IL-22:Fc alone (n = 269). Cells were fixed and stained with fluorescein isothiocyanate-labeled wheat germ agglutinin to quantify EG. Total RNA was collected, and select messenger RNAs were quantified by real time - quantitative polymerase chain reaction (RT-qPCR) using SYBR green fluorescence.ResultsExposure of HUVECs to LPS resulted in degradation of the EG compared with control (5.86 vs. 6.09 arbitrary unit [AU], p = 0.01). Interleukin-22:Fc alone also resulted in degradation of EG (5.08 vs. 6.09 AU, p = 0.01). Treatment with IL-22:Fc after LPS injury resulted in less degradation of EG compared with LPS injury alone (5.86 vs. 5.08 AU, p = 0.002). Expression of the IL-22Ra1 receptor was not different for IL-22:Fc treated compared with LPS injury only (0.69 vs. 0.86 relative expression, p = 0.10). Treatment with IL-22:Fc after LPS injury resulted in less matrix metalloproteinase 2 (0.79 vs. 1.70 relative expression, p = 0.005) and matrix metalloproteinase 14 (0.94 vs. 2.04 relative expression, p = 0.02).ConclusionsInterleukin-22:Fc alone induces EG degradation. However, IL-22:Fc treatment after LPS injury appears to mitigate EG degradation. This protective effect appears to be mediated via reduced expression of metalloproteinases.

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Empagliflozin mitigates endothelial inflammation and attenuates endoplasmic reticulum stress signaling caused by sustained glycocalyx disruption.

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