PUBLICATION
atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity
- Authors
- Wang, Y., Lu, X., Wang, X., Qiu, Q., Zhu, P., Ma, L., Ma, X., Herrmann, J., Lin, X., Wang, W., Xu, X.
- ID
- ZDB-PUB-210814-2
- Date
- 2021
- Source
- Circulation research 129(8): e166-e182 (Journal)
- Registered Authors
- Lin, Xueying, Xu, Xiaolei, Zhu, Ping
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/toxicity*
- Autophagy/drug effects*
- Autophagy-Related Protein 7/genetics
- Autophagy-Related Protein 7/metabolism
- Cardiotoxicity
- Doxorubicin/toxicity*
- Myocarditis/drug therapy*
- Myocarditis/etiology
- Myocarditis/metabolism
- Pravastatin/pharmacology
- Pravastatin/therapeutic use*
- Spironolactone/pharmacology
- Spironolactone/therapeutic use*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 34384247 Full text @ Circ. Res.
Citation
Wang, Y., Lu, X., Wang, X., Qiu, Q., Zhu, P., Ma, L., Ma, X., Herrmann, J., Lin, X., Wang, W., Xu, X. (2021) atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity. Circulation research. 129(8):e166-e182.
Abstract
Rationale: Anthracycline-induced cardiotoxicity (AIC) is a major side effect that limits the use of anthracyclines as effective chemotherapeutics. No mechanism-based therapy is available when cardiac function deteriorates.Objective: We aim to elucidate the dynamic autophagic defects in AIC, and to identify a mechanism-based therapy via both genetic and pharmacological studies. Methods and Results: Through phenotyping an adult AIC (aAIC) zebrafish model, we detected a biphasic response in autophagy: activation in the early stage and suppression in the later phase that is characterized by a decline in cardiac function. We conducted conditional genetic studies with atg7, which encodes a rate-limiting autophagy core protein, and found that atg7 overexpression (OE) leads to therapeutic effects in the late phase but deleterious effects in the early phase of aAIC. We then assessed the therapeutic effects of 37 FDA-approved autophagy activators (FAAs) using an embryonic AIC (eAIC) zebrafish model and identified spironolactone, pravastatin, and minoxidil as top-ranking drugs. We demonstrated the therapeutic efficacy of these FAAs in the aAIC model and confirmed that these drugs exert therapeutic effects in the late phase but not in the early AIC phase. Finally, we demonstrated that the time-dependent therapeutic effects are conserved in a mouse AIC model and that spironolactone and rapamycin activated autophagy in an Atg7-dependent fashion. Conclusions: Our findings suggest that atg7-based autophagy activation is an effective therapeutic avenue to reversing the decline in cardiac function in AIC, highlighting the time dependent nature of autophagy-based therapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping