AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

Junxiong Zhao; Ting Yang; Jiali Yi; Hongmin Hu; Qi Lai; Liangui Nie; Maojun Liu; Chun Chu; Jun Yang

iScience (Apr 2024)

AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis

Junxiong Zhao,
Ting Yang,
Jiali Yi,
Hongmin Hu,
Qi Lai,
Liangui Nie,
Maojun Liu,
Chun Chu,
Jun Yang

Affiliations

Junxiong Zhao: Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Ting Yang: School of Pharmaceutical Science of University of South China, Hengyang 421000, China; Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Jiali Yi: Department of Cardiology, Hunan University of Medicine General Hospital, Huaihua 418000, China
Hongmin Hu: Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Qi Lai: School of Pharmaceutical Science of University of South China, Hengyang 421000, China; Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Liangui Nie: Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Maojun Liu: Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China
Chun Chu: Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China; Corresponding author
Jun Yang: Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, China; Corresponding author

Journal volume & issue: Vol. 27, no. 4
p. 109321

Abstract

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Summary: Doxorubicin induces myocardial injury and fibrosis. Still, no effective interventions are available. AP39 is an H2S donor that explicitly targets mitochondria. This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis. Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins. Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis. In vitro experiments revealed that AP39 inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression. In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis. These results suggest that mitochondria-targeted H2S can antagonize doxorubicin-induced pyroptosis and impaired mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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