Empagliflozin-mediated protection of heparan sulfate-rich endothelial glycocalyx during vascular inflammation
Abstract
Degradation of the endothelial glycocalyx (eGC) is a hallmark of endothelial dysfunction, driving vascular inflammation and contributing to diabetes. Empagliflozin (Empa), a sodium-glucose co-transporter 2 inhibitor primarily recognized as an anti-diabetic drug, has shown pleiotropic effects on vascular health. We hypothesized that empagliflozin could attenuate eGC disruption in TNF-induced vascular inflammation. To address this, isolated murine aortae were used to study eGC degradation induced either by TNF-mediated vascular inflammation or by exogenous enzymatic removal using heparinase III (HepIII). The eGC status, with a focus on heparan sulfate, was assessed using fluorescence imaging, atomic force microscopy (AFM), bioenzymatic assays, and functional evaluation of vascular responses based on endothelium-dependent vasodilation. Changes in the nanomechanical properties of the endothelial cortex were evaluated in both wild-type and db/db mice using AFM. We found that empagliflozin attenuated the loss of eGC coverage and height in TNF-stimulated aortae and restored endothelium-dependent vasodilation. While exogenous enzymatic cleavage by Hep III disrupted the eGC layer, empagliflozin did not prevent this effect, indicating that its action is likely indirect. In contrast, inhibitors of endogenous sheddases released in response to TNF, such as sulodexide or SB-3CT, reduced eGC disruption in TNF-exposed aorta. Furthermore, Empa improved the nanomechanical properties of the…
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