Brazilin attenuates methylglyoxal‑induced endothelial injury by enhancing eIF5A hypusination and inhibiting the AMPK/mTOR‑mediated autophagy/apoptosis axis in vitro and in vivo

Le résumé fourni par la source

Methylglyoxal (MGO), a glycolytic metabolic byproduct and major precursor of advanced glycation end products (AGEs), accumulates and is critically involved in diabetes, particularly in diabetic vascular complications. In endothelial cells (ECs), MGO has been implicated in oxidative stress and inflammatory responses, and it can further induce autophagy and apoptosis. Brazilin (BZ), a natural compound, confers cytoprotection by allosterically activating deoxyhypusine hydroxylase (DOHH), thereby enhancing eukaryotic initiation factor 5A (eIF5A) hypusination, a distinctive post‑translational modification. Although BZ can mitigate vascular inflammation and regulate autophagy and apoptosis, its effects on MGO‑induced autophagy and apoptosis and the underlying mechanism remain elusive. In the present study, it was demonstrated that BZ pretreatment conferred cytoprotection by targeting DOHH and the downstream eIF5A signaling cascade, thereby suppressing activation of the AMP‑activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. Moreover, 3‑methyladenine (3‑MA) and Compound C strengthened the inhibitory effect of BZ on MGO‑induced autophagy and apoptosis. By contrast, ciclopirox, a specific inhibitor of DOHH, abolished the BZ‑mediated suppression of MGO‑induced cellular responses. The in vivo experiments further confirmed that BZ suppresses MGO‑triggered autophagy and apoptosis. Using db/db mice to mimic the diabetic microenvironment, it was further found that DOHH inhibition reversed the BZ‑mediated suppression of autophagy and apoptosis. Collectively, the findings of the present study reveal a DOHH/eIF5A‑AMPK/mTOR axis through which BZ antagonizes MGO‑induced autophagy and apoptosis, shedding new light on the pharmacological mechanism of BZ and underscoring its therapeutic potential for diabetic vascular complications.

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