Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 2012 Oct;32(10):2531-9
Date
08/11/2012Pubmed ID
22879582Pubmed Central ID
PMC3570053DOI
10.1161/ATVBAHA.112.256024Scopus ID
2-s2.0-84866619132 (requires institutional sign-in at Scopus site) 81 CitationsAbstract
OBJECTIVE: Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM). Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking.
METHODS AND RESULTS: In 122 human subjects (60 with T2DM, 62 without T2DM), we measured endothelial function by brachial artery ultrasound (flow mediated dilation) and digital pulse amplitude tonometery. Endothelial function in arterioles isolated from gluteal subcutaneous adipose was measured by videomicroscopy. In arterioles and mononuclear cells, we measured inner mitochondrial membrane potential (Δψ(m)), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM subjects versus control subjects. Δψ(m) magnitude was larger and mitochondrial mass was lower in arterioles and mononuclear cells in T2DM. Mononuclear mitochondrial mass correlated with flow-mediated dilation and pulse amplitude tonometery (ρ=0.38 and 0.33, P=0.001 and 0.02, respectively), and mononuclear mitochondrial superoxide production inversely correlated with flow-mediated dilation (ρ=-0.58, P=0.03). Low doses of 2 different mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenyl hydrazone and 2,4-dinitrophenol) that reduce Δψ(m) magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels in T2DM arterioles.
CONCLUSIONS: Mitochondrial dysfunction may play a central role in the impairment of endothelial dysfunction in T2DM.
Author List
Kizhakekuttu TJ, Wang J, Dharmashankar K, Ying R, Gutterman DD, Vita JA, Widlansky MEAuthor
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
2,4-DinitrophenolAdult
Arterioles
Brachial Artery
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Case-Control Studies
Diabetes Mellitus, Type 2
Endothelium, Vascular
Female
Humans
Male
Membrane Potential, Mitochondrial
Middle Aged
Mitochondria
Organophosphorus Compounds
Piperidines
Pulse Wave Analysis
Superoxides
Ultrasonography
Uncoupling Agents
