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- Title
425-P: Inhibition of miR-181c Rescues Diabetes-Impaired Angiogenesis.
- Authors
SOLLY, EMMA; HOURIGAN, SAMUEL T.; MULANGALA, JOCELYNE; PSALTIS, PETER J.; BARTOLO, BELINDA DI; NG, MARTIN; NICHOLLS, STEPHEN; BURSILL, CHRISTINA; TAN, JOANNE T.M.
- Abstract
Diabetic vascular complications are characterized by impaired angiogenic responses to ischemia, resulting in delayed healing following tissue injury. MicroRNAs (miRNAs), small non-coding RNAs that target gene expression, regulate angiogenesis in a time-dependent manner. Using a miRNA array approach, we discovered that miR-181c was regulated by angiogenic stimuli but had no previous reported role in diabetes. We sought to elucidate the role of miR-181c in diabetes-impaired angiogenesis. We found that miR-181c was inhibited in endothelial cells (ECs) exposed to hypoxia but were, conversely, elevated in high glucose. To assess the importance of miR-181c in angiogenesis, ECs were transfected with mimics or antimiRs to mimic or suppress miR-181c activity respectively. Cells with increased miR-181c activity had a reduced capacity to form tubules and lower VEGFA protein levels. Conversely, suppression of miR-181c activity augmented tubule formation and VEGFA expression. This suggests that miR-181c plays an inhibitory role in angiogenesis, at least in part, through VEGFA regulation. In vivo, miR-181c was temporally tracked following ischemic induction in the hindlimb. Early post-ischemia, when angiogenesis is important, diabetic mice had elevated miR-181c levels compared to nondiabetic controls. However, at later timepoints, miR-181c levels dropped to levels similar to nondiabetic mice. This indicates that miR-181c suppression may be critical to facilitate early responses to ischemia. Diabetic mice were injected with antimiR-181c or antimiR-Neg to determine if miR-181c knockdown rescues diabetes-impaired angiogenesis. Inhibition of miR-181c completely rescued diabetes-impaired blood flow reperfusion, restoring it back to that of nondiabetic levels. Taken together, this study has identified that miR-181c plays a key role in the regulation of angiogenesis in ischemia and in diabetes. This highlights a potential new therapeutic approach for the treatment of diabetic vascular complications. Disclosure: E. Solly: None. S.T. Hourigan: None. J. Mulangala: None. P.J. Psaltis: None. B. Di Bartolo: None. M. Ng: None. S. Nicholls: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Cerenis, CSL Behring, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Omthera, Pfizer Inc., Resverlogix Corp., Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; Amgen Inc., AstraZeneca, Athernova, Cerenis, Eli Lilly and Company, InfraReDx, Novartis Pharmaceuticals Corporation, Resverlogix Corp., Sanofi. C. Bursill: None. J.T.M. Tan: None. Funding: Diabetes Australia
- Publication
Diabetes, 2019, Vol 68, pN.PAG
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db19-425-P