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https://hdl.handle.net/2440/119313
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Type: | Journal article |
Title: | Fenofibrate rescues diabetes-related impairment of ischemia-mediated angiogenesis by PPARα-independent modulation of thioredoxin-interacting protein |
Author: | Yuan, J. Tan, J.T.M. Rajamani, K. Solly, E.L. King, E.J. Lecce, L. Simpson, P.J.L. Lam, Y.T. Jenkins, A.J. Bursill, C.A. Keech, A.C. Ng, M.K.C. |
Citation: | Diabetes, 2019; 68(5):1040-1053 |
Publisher: | American Diabetes Association |
Issue Date: | 2019 |
ISSN: | 0012-1797 1939-327X |
Statement of Responsibility: | Jun Yuan, Joanne T.M. Tan, Kushwin Rajamani, Emma L. Solly, Emily J. King, Laura Lecce, Philippa J.L. Simpson, Yuen Ting Lam, Alicia J. Jenkins, Christina A. Bursill, Anthony C. Keech and Martin K.C. Ng |
Abstract: | Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduces lower limb amputations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose-impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate. |
Keywords: | Hindlimb Animals Mice Ischemia Diabetes Mellitus, Experimental Neovascularization, Pathologic Glucose Carrier Proteins Signal Transduction Fenofibrate |
Rights: | © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. |
DOI: | 10.2337/db17-0926 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/512299 http://purl.org/au-research/grants/nhmrc/1066541 |
Published version: | http://dx.doi.org/10.2337/db17-0926 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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