Abstract 18059: Microrna-126 and Microrna-132 Abrogates Deleterious Effects of Diabetes-Induced Impaired Angiogenesis
Background: Diabetes-induced microvascular abnormalities are implicated in altering cardiac function and structure, a condition referred as diabetic microangiopathy in heart (DMAH). Endothelial-enriched microRNAs (angiomiRs) have been recently demonstrated to play a major role in regulating angiogenesis. However, their pathophysiological role in development of DMAH is elusive.Objective: To investigate the modulation of angiomiRs (miR-126, miR-132) with evolution of DMAH and demonstrate if restoration of angiomiRs can improve functional properties of high glucose treated endothelial cells.
Methods & Results: Cardiac tissues were collected from type-2 diabetic mice (BKS.Cg-m+/+Leprdb/J) every 4Wks, from 8 to 32Wks of age. qPCR revealed significant downregulation of miR-126 and -132 starting at 12Wks and continued till 32Wks (miR-126: 0.30±0.03; miR-132: 0.22±0.05,p<0.001 vs. age matched non-diabetic). This was associated with concomitant dysfunction of cardiac functions (assessed through echocardiography). Western blotting analysis confirmed marked dysregulation of VEGF and p120RasGap (P<0.05 vs. non-diabetic), the target proteins for miR-126 and -132, respectively. Interestingly, immunohistochemical analysis did not show any noticeable changes in the capillaries and arterioles until 20Wks in diabetes. To determine if restoration of miR-126 and -132 could reduce the development of DMAH, high glucose (HG)-treated Human Umbilical Vein Endothelial Cells (HUVECs) were transfected with either miR-126 or -132 mimics. Results showed that restoration of both the miRs markedly improved angiogenesis, assessed by tube formation assay (NG-Control- 8824±212; HG-Control: 3570±304; HG-126: 8970±184; HG-132: 7227±228), proliferation (CyQUANT cell proliferation assay) and reduced cell death (caspase-3/7 assay), p<0.05 for all the parameters. Of note, overexpression of miR-126 alone tends to restore the expression of miR-132 and vice versa in HG-treated HUVECs, suggesting an orchestrated role of miRs in regulating angiogenesis.
Conclusion: Modulation of miRs occur much earlier before the development of DMAH and restoration of DMAH from early stages in HUVECs exposed to high glucose markedly improved their angiogenic potential.
Author Disclosures: S. Rawal: None. E. Munasinghe: None. A. Shindikar: None. P. Manning: None. R. Katare: Research Grant; Modest; Heart Foundation New Zealand.
- © 2016 by American Heart Association, Inc.