alexa Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Velmurugan GV, Sundaresan NR, Gupta MP, White C

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Abstract AIMS: In type 2 diabetes, antioxidant depletion contributes to increased oxidative stress in the microvasculature. The current study was designed to assess how oxidative stress contributes to functional changes in the microvasculature, and determine the importance, and the effects of pharmacologically targeting, the transcription factor Nrf2. METHODS AND RESULTS: Pressure myography was used to measure myogenic constriction in mesenteric arterioles from diabetic (db/db) and non-diabetic (db/m) mice. Compared with db/m, myogenic constriction was larger in db/db, independent of the endothelial cell layer, and directly correlated with elevated basal and pressure-induced reactive oxygen species (ROS) production. Nrf2 was depleted in db/db vessels and associated with down-regulation of Nrf2-regulated genes. Notably, expression of GCLC and GCLM, enzymes important for glutathione (GSH) synthesis, was dramatically reduced, as was total cellular GSH. Normal myogenic function was restored to db/db arterioles by incubation with cell-permeant GSH. Similarly, the db/db myogenic phenotype was recapitulated in the db/m vessels by pharmacological GSH depletion. Treatment with the Nrf2-activator sulforaphane increased Nrf2 and promoted its nuclear localization and increased GCLC and GCLM expression in both db/m and db/db. Sulforaphane dramatically lowered ROS signalling in db/db and reduced myogenic tone to levels similar to that seen in db/m vessels. CONCLUSION: Depleted Nrf2 and expression of its dependent genes compromises antioxidant capacity resulting in dysfunctional myogenic tone in diabetes that is reversed by the Nrf2-activator sulforaphane. This article was published in Cardiovasc Res and referenced in Journal of Diabetes & Metabolism

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