Article

Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus

Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118., USA.
Circulation (Impact Factor: 14.43). 07/2011; 124(4):444-53. DOI: 10.1161/CIRCULATIONAHA.110.014506
Source: PubMed

ABSTRACT

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

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    • "Directly related to this, Shenouda et al. reported mitochondrial fragmentation and increased levels of FIS1 protein in venous endothelial cells from patients with T2DM, as well as increased abundance of FIS1 and DRP1 proteins in cultured human aortic endothelial cells incubated with high glucose medium (Shenouda et al. 2011). Altered mitochondrial dynamics were associated with increased mitochondrial ROS production, and silencing FIS1 or DRP1 expression with siRNA prevented high glucose-induced alterations in mitochondrial networks and ROS production (Shenouda et al. 2011). In atherosclerosis, VSMCs develop a highly proliferative and synthetic phenotype in a process triggered by PDGF (Yu et al. 2001;Perez et al. 2010). "
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