Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Cardiovasc Res. 2013 Oct 1;100(1):143-50. doi: 10.1093/cvr/cvt125. Epub 2013 May 27.
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.
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.
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.
在 2 型糖尿病中，抗氧化剂耗竭导致微血管中氧化应激增加。本研究旨在评估氧化应激如何导致微血管功能发生变化，并确定转录因子 Nrf2 的重要性及其作为药物靶点的效果。
使用压力肌动描记术测量来自糖尿病（db/db）和非糖尿病（db/m）小鼠肠系膜小动脉的肌源性收缩。与 db/m 相比，db/db 中小动脉的肌源性收缩更大，且独立于内皮细胞层，并且与基础和压力诱导的活性氧（ROS）产生升高直接相关。db/db 血管中 Nrf2 耗竭，并伴有 Nrf2 调节基因的下调。值得注意的是，谷胱甘肽（GSH）合成的重要酶 GCLC 和 GCLM 的表达明显降低，细胞内总 GSH 也降低。用细胞通透 GSH 孵育可使 db/db 动脉的正常肌源性功能恢复正常。类似地，通过药理学 GSH 耗竭可在 db/m 血管中重现 db/db 的肌源性表型。Nrf2 激活剂萝卜硫素处理可增加 Nrf2 并促进其核定位，并增加 db/m 和 db/db 中的 GCLC 和 GCLM 表达。萝卜硫素可显著降低 db/db 中的 ROS 信号，并将肌源性张力降低至与 db/m 血管相似的水平。
Nrf2 耗竭和其依赖基因的表达降低了抗氧化能力，导致糖尿病中肌源性张力功能障碍，而 Nrf2 激活剂萝卜硫素可逆转这种情况。
