AMP-activated protein kinase rescues the angiogenic functions of endothelial progenitor cells via manganese superoxide dismutase induction in type 1 diabetes.

Abstract

Endothelial progenitor cells (EPCs) play an essential role in angiogenesis but are functionally impaired in diabetes. We recently reported that decreased expression of manganese superoxide dismutase (MnSOD) critically contributes to diabetic EPC dysfunction. AMP-activated protein kinase (AMPK) activation has been shown to induce MnSOD and suppress hyperglycemia-induced mitochondrial ROS production in endothelial cells. However, whether AMPK protects EPCs from oxidative stress in diabetes is unknown. We tested the hypothesis that AMPK activation rescues impaired EPC functions through MnSOD induction in type 1 diabetes. Bone marrow-derived EPCs from adult male streptozotocin-induced diabetic mice and normal controls were used. AMPK activity was decreased in diabetic EPCs, indicated by reduced AMPK and acetyl-CoA carboxylase phosphorylation. AMPK activation by treating diabetic EPCs with its selective agonist AICAR rescued their in vitro functions, including Matrigel tube formation, adhesion, and migration. Furthermore, AICAR restored the decreased MnSOD protein and enzymatic activity and suppressed the mitochondrial superoxide level in diabetic EPCs, indicated by MitoSOX flow cytometry. These beneficial effects of AICAR on MnSOD and EPC functions were significantly attenuated by silencing MnSOD or AMPK antagonist compound C pretreatment. Finally, the expression of protein phosphatase 2A, a key enzyme for AMPK dephosphorylation and inactivation, was increased in diabetic EPCs, and its inhibition by siRNA or okadaic acid reversed the deficient AMPK activation and MnSOD level in diabetic EPCs. These findings demonstrate for the first time that AMPK activation rescues impaired EPC functions and suppresses mitochondrial superoxide by inducing MnSOD in type 1 diabetes.

• Authors: Xiao-Rong Wang, Ming-Wei Zhang, Dan-Dan Chen, Yun Zhang, Alex F Chen
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 300 Issue 6 Pg. E1135-45 (Jun 2011) ISSN: 1522-1555 [Electronic] United States
• PMID: 21427411 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Ribonucleotides
• Aminoimidazole Carboxamide
• Superoxide Dismutase
• Cyclic AMP-Dependent Protein Kinases
• Protein Phosphatase 2
• AICA ribonucleotide

Topics

• Adenoviridae (genetics)
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology)
• Animals
• Blotting, Western
• Bone Marrow Cells (physiology)
• Bone Marrow Transplantation
• Cell Adhesion
• Cell Movement
• Cells, Cultured
• Cyclic AMP-Dependent Protein Kinases (physiology)
• Diabetes Mellitus, Experimental (enzymology, metabolism)
• Diabetes Mellitus, Type 1 (enzymology, metabolism)
• Endothelial Cells (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Microtubules (physiology)
• Mitochondria (metabolism)
• Neovascularization, Physiologic (physiology)
• Protein Phosphatase 2 (metabolism)
• RNA, Small Interfering (genetics)
• Ribonucleotides (pharmacology)
• Stem Cells (physiology)
• Superoxide Dismutase (biosynthesis)
• Transfection