PUBLICATION
Accumulation of newly synthesized docosahexaenoic acid plays an essential role in heart regeneration
- Authors
- Tang, Z., Sun, Z., Yang, C., Gong, Q., Liu, Z., Chen, N., Liu, K., Wang, Y., Zhao, T., Ye, S., Zhuang, L., Lin, J., Tan, W.Q., Peng, J., Chen, J.
- ID
- ZDB-PUB-250825-6
- Date
- 2025
- Source
- Protein & cell : (Journal)
- Registered Authors
- Peng, Jinrong
- Keywords
- DHA, PPARD, heart regeneration, mouse, zebrafish
- MeSH Terms
-
- Animals
- Docosahexaenoic Acids*/biosynthesis
- Docosahexaenoic Acids*/metabolism
- Docosahexaenoic Acids*/pharmacology
- Fatty Acid Desaturases/antagonists & inhibitors
- Fatty Acid Desaturases/genetics
- Fatty Acid Desaturases/metabolism
- Heart*/physiology
- Mice
- Myocardial Infarction/metabolism
- Myocardial Infarction/pathology
- Myocytes, Cardiac/metabolism
- Regeneration*/drug effects
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 40851370 Full text @ Protein Cell
Citation
Tang, Z., Sun, Z., Yang, C., Gong, Q., Liu, Z., Chen, N., Liu, K., Wang, Y., Zhao, T., Ye, S., Zhuang, L., Lin, J., Tan, W.Q., Peng, J., Chen, J. (2025) Accumulation of newly synthesized docosahexaenoic acid plays an essential role in heart regeneration. Protein & cell. :.
Abstract
Adult zebrafish and neonatal mice can fully regenerate their hearts after partial amputation through proliferation of pre-existing cardiomyocytes (CMs). However, the adult mammalian heart has limited regenerative capability following cardiac damage. The reason for this phenomenon remains elusive. Here, we find that docosahexaenoic acid (DHA) is accumulated only in the injury hearts of zebrafish and neonatal mice, but not of adult mice, which coincides with the upregulation of DHA synthesis genes in CMs, fibrobasts and macrophages near the injury areas. Inhibition of Fads2, a DHA synthesis enzyme, impairs heart regeneration in both zebrafish and neonatal mice. Injection of DHA remodels transcriptome from injury response to regeneration response and improves cardiac function in adult mice after myocardial infarction. Interestingly, DHA facilitates CM proliferation, but inhibits fibrosis and inflammation. Mechanistically, only DHA, but not oleic acid (OA), can trigger the peroxisome proliferator-activated receptor d (PPARD) to bind to the promoter regions of heart regeneration related genes such as: Mef2d, Phlda3 and Txndc5 to regulate their expression. Molecular docking, molecular dynamics simulations and mutagenesis experiments suggest that DHA binds to PPARD in a distinct manner compared to OA, which may help explain their differing abilities to influence the expression of heart regeneration genes. Our findings demonstrate that the DHA signal plays an essential and evolutionarily conserved role in heart regeneration and provide a therapeutic potential for myocardial infarction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping