Journal article
Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischaemia–reperfusion injury by elevating plasma adiponectin
- Abstract:
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Aims
Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest.
Methods and results
Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischaemia–reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in wild-type but not adiponectin knockout mice attenuated myocardial ischaemia–reperfusion injury.
Conclusion
Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 3.8MB, Terms of use)
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- Publisher copy:
- 10.1093/cvr/cvae017
Authors
- Publisher:
- Oxford University Press
- Journal:
- Cardiovascular Research More from this journal
- Volume:
- 120
- Issue:
- 8
- Pages:
- 954–970
- Place of publication:
- England
- Publication date:
- 2024-01-22
- Acceptance date:
- 2023-11-30
- DOI:
- EISSN:
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1755-3245
- ISSN:
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0008-6363
- Pmid:
-
38252884
- Language:
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English
- Keywords:
- Pubs id:
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1606600
- Local pid:
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pubs:1606600
- Deposit date:
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2024-02-23
Terms of use
- Copyright holder:
- Fu et al.
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Notes:
- This research was funded in part by the Wellcome Trust. For the purpose of Open Access the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
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