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Defective Nrf2‐Dependent Redox Signaling Contributes To Microvascular Dysfunction In Type 2 Diabetes
Author(s) -
Velmurugan Gopal V,
White Carl
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.924.8
Subject(s) - gclc , gclm , oxidative stress , glutathione , reactive oxygen species , endocrinology , medicine , chemistry , microbiology and biotechnology , activator (genetics) , sulforaphane , biology , biochemistry , gene , enzyme
In type‐2 diabetes, antioxidant depletion contributes to increased oxidative stress in the microvasculature. However, the mechanisms and physiological consequences are poorly understood. The objective of this study is to assess how oxidative stress contributes to functional changes in the diabetic microvasculature and to determine the effective role of transcription factor Nrf2. Myogenic tone was larger in diabetic (db/db) vessels and was directly correlated with elevated basal and pressure‐induced reactive oxygen species (ROS). Levels of Nrf2 and Nrf2‐regulated genes were downregulated in db/db vessels. Notably, expression of GCLC and GCLM, enzymes important for glutathione (GSH) synthesis and total GSH were significantly reduced. 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 nondiabetic (db/m) vessels by GSH depletion. Treatment with the Nrf2‐activator sulforaphane increased GCLC, GCLM expression levels in db/db and dramatically lowered ROS and myogenic tone to db/m levels. In conclusion, depleted Nrf2 and its dependent genes compromises antioxidant capacity resulting in dysfunctional myogenic tone in diabetes. Defective Nrf2 signaling and its physiological consequences are rescued by sulforaphane, highlighting the compounds potential as a therapeutic tool.