Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus
Open accessAbstract
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.
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Unrecognized heart failure is frequent in type 2 diabetes: in a cross-sectional study of patients aged 60 years or older with type 2 diabetes without known heart failure, heart failure was present in 28% of patients, about 25% HFrEF and about 75% HFpEF.
“Unrecognized HF is frequent in T2DM: a cross-sectional study in patients aged ≥60 years with T2DM without known HF using a standardized diagnostic work-up, including medical history, physical examination, ECG, and echocardiography, indicated that HF was present in 28% of patients (∼25% HFrEF and ∼75% HFpEF).[460][461][462][463][464]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [460]
Observational studies have consistently demonstrated a two- to four-fold increased risk of heart failure in individuals with diabetes compared with those without diabetes.
“Observational studies have consistently demonstrated a two-to four-fold increased risk of HF in individuals with diabetes compared with those without diabetes.[460][461][462][463]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [460]
Mitochondrial dysregulation is implicated in impaired arterial function in human diabetes mellitus.
“and human diabetes mellitus (166)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [166]
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- Authors
- Shenouda, S. M., Widlansky, M. E., Chen, K., Xu, G., Holbrook, M., Tabit, C. E., Hamburg, N. M., Frame, A. A., Caiano, T. L., Kluge, M. A., Duess, M.-A., Levit, A., Kim, B., Hartman, M.-L., Joseph, L., Shirihai, O. S., & Vita, J. A.
- Affiliations
- Boston University (US)
- Venue
- Circulation
- Published
- 2011-07-26
- Volume
- 124
- Issue
- 4
- Pages
- 444-453
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3149100
- OpenAlex
- W2074710857
- Cited by
- 570
- References
- 28
- Citations by year
- 2026: 27 · 2025: 40 · 2024: 39 · 2023: 45 · 2022: 42 · 2021: 47 · 2020: 45 · 2019: 30 · 2018: 46 · 2017: 34 · 2016: 37 · 2015: 27 · 2014: 49 · 2013: 34 · 2012: 24
- FWCI
- 14.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL060886, R01HL102299, HL081587, P50HL083801, HL083269, K12HL083781, P01HL081587, R01HL075795, HL75795, R01HL083269, HL083801, HL102299, K23HL089326)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK035914, R56DK035914, R01DK074778, R01DK056690, DK035914, DK074778)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial dynamics, mitochondrial fission, endothelial dysfunction, diabetes mellitus, Fis1, Drp1, reactive oxygen species, endothelial nitric oxide synthase, cGMP signaling, high glucose, atherosclerosis, mitochondrial fragmentation
- MeSH terms
- Adult, Aorta, Cell Line, Cells, Cultured, Diabetes Mellitus, Type 2, Endothelium, Vascular, Female, Glucose, Cyclic GMP, Humans, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Mitochondria, Body Mass Index, Free Radical Scavengers, Reactive Oxygen Species, GTP Phosphohydrolases, Mitochondrial Proteins, Dynamins, Nitric Oxide Synthase Type III
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