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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

08/11/2012

Pubmed ID

22879582

Pubmed Central ID

PMC3570053

DOI

10.1161/ATVBAHA.112.256024

Scopus ID

2-s2.0-84866619132   61 Citations

Abstract

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 ME

Authors

David D. Gutterman MD Sr Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

2,4-Dinitrophenol
Adult
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
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d