Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase

Varadarajan Sudhahar, Norifumi Urao, Jin Oshikawa, Ronald D. McKinney, Roxana M. Llanos, Julian F.B. Mercer, Masuko Ushio-Fukai, Tohru Fukai

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Vasculopathy is a major complication of diabetes; however, molecular mechanisms mediating the development of vasculopathy and potential strategies for prevention have not been identified. We have previously reported that C-peptide prevents diabetic vasculopathy by inhibiting reactive oxygen species (ROS)-mediated endothelial apoptosis. To gain further insight into ROS-dependent mechanism of diabetic vasculopathy and its prevention, we studied high glucose-induced cytosolic and mitochondrial ROS production and its effect on altered mitochondrial dynamics and apoptosis. For the therapeutic strategy, we investigated the vasoprotective mechanism of C-peptide against hyperglycemia-induced endothelial damage through the AMP-activated protein kinase a (AMPKα) pathway using human umbilical vein endothelial cells and aorta of diabetic mice. High glucose (33 mmol/L) increased intracellular ROS through a mechanism involving interregulation between cytosolic and mitochondrial ROS generation. C-peptide (1 nmol/L) activation of AMPKα inhibited high glucose-induced ROS generation, mitochondrial fission, mitochondrial membrane potential collapse, and endothelial cell apoptosis. Additionally, the AMPK activator 5-aminoimidazole-4-carboxamide 1-b-D-ribofuranoside and the antihyperglycemic drug metformin mimicked protective effects of C-peptide. C-peptide replacement therapy normalized hyperglycemiainduced AMPKα dephosphorylation, ROS generation, and mitochondrial disorganization in aorta of diabetic mice. These findings highlight a novel mechanism by which C-peptide activates AMPKα and protects against hyperglycemia-induced vasculopathy.

Original languageEnglish (US)
Pages (from-to)3839-3850
Number of pages12
JournalDiabetes
Volume62
Issue number11
DOIs
StatePublished - Nov 1 2013

Fingerprint

C-Peptide
Superoxide Dismutase
AMP-Activated Protein Kinases
Copper
Reactive Oxygen Species
Mitochondrial Dynamics
Apoptosis
Glucose
Hyperglycemia
Aorta
Aminoimidazole Carboxamide
Mitochondrial Membrane Potential
Metformin
Human Umbilical Vein Endothelial Cells
Diabetes Complications
Hypoglycemic Agents
Endothelial Cells
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. / Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin; McKinney, Ronald D.; Llanos, Roxana M.; Mercer, Julian F.B.; Ushio-Fukai, Masuko; Fukai, Tohru.

In: Diabetes, Vol. 62, No. 11, 01.11.2013, p. 3839-3850.

Research output: Contribution to journalArticle

Sudhahar, Varadarajan ; Urao, Norifumi ; Oshikawa, Jin ; McKinney, Ronald D. ; Llanos, Roxana M. ; Mercer, Julian F.B. ; Ushio-Fukai, Masuko ; Fukai, Tohru. / Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. In: Diabetes. 2013 ; Vol. 62, No. 11. pp. 3839-3850.
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