Adverse Alterations in Mitochondrial Function Contribute to Type 2 Diabetes Mellitus–Related Endothelial Dysfunction in Humans

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 10; pp. 2531 - 2539
• Main Authors: Kizhakekuttu, Tinoy J., Wang, Jingli, Dharmashankar, Kodlipet, Ying, Rong, Gutterman, David D., Vita, Joseph A., Widlansky, Michael E.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.2012; Lippincott Williams & Wilkins
• Subjects: 2,4-Dinitrophenol - pharmacology; Adult; Arterioles - diagnostic imaging; Arterioles - drug effects; Arterioles - physiopathology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Brachial Artery - diagnostic imaging; Brachial Artery - drug effects; Brachial Artery - physiopathology; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cardiology. Vascular system; Case-Control Studies; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium, Vascular - diagnostic imaging; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Female; Humans; Male; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Middle Aged; Mitochondria - drug effects; Mitochondria - physiology; Organophosphorus Compounds - pharmacology; Piperidines - pharmacology; Pulse Wave Analysis; Superoxides - metabolism; Ultrasonography; Uncoupling Agents - pharmacology; Endocrinopathy; Type 2 diabetes; Human; Oxidative stress; NO; Metabolic diseases; Cardiovascular disease; Endothelium; Vascular disease; Mitochondria; Atherosclerosis; Endothelial dysfunction; diabetes mellitus type 2
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.112.256024

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 (Δψm), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM subjects versus control subjects. Δψm 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 Δψm magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels in T2DM arterioles. CONCLUSION—Mitochondrial dysfunction may play a central role in the impairment of endothelial dysfunction in T2DM.