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Am J Physiol Endocrinol Metab. 2017 Oct 1;313(4):E391-E401. doi: 10.1152/ajpendo.00073.2017. Epub 2017 Jul 11.

MiR-27b augments bone marrow progenitor cell survival via suppressing the mitochondrial apoptotic pathway in Type 2 diabetes.

Author information

1
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.
2
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan.
3
Departments of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, Michigan.
4
Integrated Biosciences, Wayne State University, Detroit, Michigan.
5
Clinical Research Institute, Department of Cardiology and Endocrinology, The Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China.
6
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
7
Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
8
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan; jiemei.wang@wayne.edu.

Abstract

Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogenous noncoding RNAs that regulate gene expression at the posttranscriptional level, but their roles in BMPC-mediated angiogenesis are incompletely understood. In the present study, we tested the hypothesis that the proangiogenic miR-27b inhibits BMPC apoptosis in Type 2 diabetes. Bone marrow-derived EPCs from adult male Type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased after 24 h of exposure to methylglyoxal (MGO) or oxidized low-density lipoprotein but not high glucose, advanced glycation end products, the reactive oxygen species generator LY83583, or H2O2 The increase in BMPC apoptosis in the diabetic mice was rescued following transfection with a miR-27b mimic, and the increased apoptosis induced by MGO was also rescued by the miR-27b mimic. p53 protein expression and the Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice, both of which were suppressed by miR-27b. Furthermore, mitochondrial respiration, as measured by oxygen consumption rate, was enhanced by miR-27b in diabetic BMPCs, with concomitant decrease of mitochondrial Bax/Bcl-2 ratio. The 3' UTR binding assays revealed that both Bax, and its activator RUNX1, were direct targets of miR-27b, suggesting that miR-27b inhibits Bax expression in both direct and indirect manners. miR-27b prevents EPC apoptosis in Type 2 diabetic mice, at least in part, by suppressing p53 and the Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing BMPC dysfunction in diabetes for successful autologous cell therapy.

KEYWORDS:

Type 2 diabetes; apoptosis; microRNA; progenitor cells

PMID:
28698281
PMCID:
PMC5668595
DOI:
10.1152/ajpendo.00073.2017
[Indexed for MEDLINE]
Free PMC Article

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