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Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 2011 Jul 26;124(4):444-53

Date

07/13/2011

Pubmed ID

21747057

Pubmed Central ID

PMC3149100

DOI

10.1161/CIRCULATIONAHA.110.014506

Scopus ID

2-s2.0-79961021186   267 Citations

Abstract

BACKGROUND: Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species. We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes mellitus.

METHODS AND RESULTS: We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1; P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared with healthy control subjects (n=9). In cultured human aortic endothelial cells exposed to 30 mmol/L glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial reactive oxygen species production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase and cGMP production. Silencing Fis1 or Drp1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, reactive oxygen species production, endothelial nitric oxide synthase activation, and cGMP production. An intracellular reactive oxygen species scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased reactive oxygen species.

CONCLUSION: These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.

Author List

Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA, Duess MA, Levit A, Kim B, Hartman ML, Joseph L, Shirihai OS, Vita JA

Author

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

Adult
Aorta
Body Mass Index
Cell Line
Cells, Cultured
Cyclic GMP
Diabetes Mellitus, Type 2
Endothelium, Vascular
Female
Free Radical Scavengers
GTP Phosphohydrolases
Glucose
Humans
Male
Membrane Proteins
Microtubule-Associated Proteins
Middle Aged
Mitochondria
Mitochondrial Proteins
Nitric Oxide Synthase Type III
Reactive Oxygen Species
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d