Journal article
Activation of HIF1α rescues the hypoxic response and reverses metabolic dysfunction in the diabetic heart
- Abstract:
- Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart.In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment.In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. <i>In vivo</i> this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Accepted manuscript, 1.0MB, Terms of use)
-
- Publisher copy:
- 10.2337/db21-0398
Authors
- Publisher:
- American Diabetes Association
- Journal:
- Diabetes More from this journal
- Volume:
- 70
- Issue:
- 11
- Pages:
- 2518-2531
- Publication date:
- 2021-09-15
- Acceptance date:
- 2021-08-27
- DOI:
- EISSN:
-
1939-327X
- ISSN:
-
0012-1797
- Pmid:
-
34526367
- Language:
-
English
- Keywords:
- Pubs id:
-
1196710
- Local pid:
-
pubs:1196710
- Deposit date:
-
2021-11-01
Terms of use
- Copyright holder:
- American Diabetes Association
- Copyright date:
- 2021
- Rights statement:
- © 2021 by the American Diabetes Association https://www.diabetesjournals.org/content/license 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 https://www.diabetesjournals.org/content/license.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from American Diabetes Association at: https://doi.org/10.2337/db21-0398
If you are the owner of this record, you can report an update to it here: Report update to this record