Journal
CLINICAL SCIENCE
Volume 124, Issue 5-6, Pages 403-411Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20120239
Keywords
AMP-activated protein kinase (AMPK); coronary artery disease (CAD); diabetes; endothelium; mitochondrion; oxidative stress
Categories
Funding
- British Heart Foundation [RG/07/005/23633]
- European Union
- Seventh Framework Programme 'EU-MASCARA'
- Wellcome Trust Cardiovascular Functional Genomics Initiative [066780/2/012]
- Diabetes UK [11/0004309] Funding Source: researchfish
- Medical Research Council [MC_U105663142] Funding Source: researchfish
- MRC [MC_U105663142] Funding Source: UKRI
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The aim of the present study was to determine whether the endothelial dysfunction associated with CAD (coronary artery disease) and T2D (Type 2 diabetes mellitus) is concomitant with elevated mtROS (mitochondrial reactive oxygen species) production in the endothelium and establish if this, in turn, regulates the activity of endothelial AMPK (AMP-activated protein kinase). We investigated endothelial function, mtROS production and AMPK activation in saphenous veins from patients with advanced CAD. Endothelium-dependent vasodilation was impaired in patients with CAD and T2D relative to those with CAD alone. Levels of mitochondrial H2O2 and activity of AMPK were significantly elevated in primary HSVECs (human saphenous vein endothelial cells) from patients with CAD and T2D compared with those from patients with CAD alone. Incubation with the mitochondria-targeted antioxidant, MitoQ(10) significantly reduced AMPK activity in HSVECs from patients with CAD and T2D but not in cells from patients with CAD alone. Elevated mtROS production in the endothelium of patients with CAD and T2D increases AMPK activation, supporting a role for the kinase in defence against oxidative stress. Further investigation is required to determine whether pharmacological activators of AMPK will prove beneficial in the attenuation of endothelial dysfunction in patients with CAD and T2D.
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