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AP39 alleviates HHCY-induced myocardial remodeling by regulating FUNDC1-mediated mitochondrial dynamics via
Yaling Li1, Jianghe Jiang1, Yingchun Song1
1Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Insights
Hyperhomocysteinemia (HHCY) causes heart damage by impairing mitochondria and promoting cell aging. AP39, a hydrogen sulfide donor, protects the heart by restoring mitochondrial function and reducing cell senescence.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Cellular Aging
Background:
- Hyperhomocysteinemia (HHCY) is a known cardiovascular risk factor.
- Molecular mechanisms of HHCY-induced myocardial remodeling are not fully understood.
- Mitochondrial dysfunction and cardiomyocyte senescence are implicated in HHCY pathology.
Purpose of the Study:
- Investigate the role of mitochondrial dysfunction and cardiomyocyte senescence in HHCY-associated myocardial remodeling.
- Explore the protective effects of AP39, a mitochondria-targeted hydrogen sulfide (H₂S) donor, against HHCY-induced cardiac damage.
Main Methods:
- Integrated approach: retrospective clinical analysis, in vivo animal models, and in vitro cellular experiments.
- Assessed associations between homocysteine (HCY) levels and left ventricular hypertrophy in hypertensive patients.
- Evaluated cardiac function, fibrosis, senescence, and mitochondrial dynamics in HHCY models with and without AP39.
Main Results:
- HHCY significantly associated with left ventricular hypertrophy; elevated HCY increased hypertrophy risk.
- HHCY impaired cardiac function, increased fibrosis and cardiomyocyte senescence in animal models.
- AP39 treatment ameliorated HHCY-induced cardiac pathology by restoring mitochondrial homeostasis via the FUNDC1-DRP1 axis.
Conclusions:
- AP39 protects against HHCY-induced myocardial remodeling by preserving mitochondrial homeostasis.
- The mechanism involves NEDD8/CUL4B-dependent S-sulfhydration, regulating the FUNDC1-DRP1 interaction.
- This study identifies a novel therapeutic target and provides mechanistic insights into HHCY-associated cardiovascular disease.
Introduction:
Hyperhomocysteinemia (HHCY) is a well-recognized risk factor for cardiovascular diseases; however, the molecular mechanisms underlying HHCY-induced myocardial remodeling remain unclear. This study aimed to investigate the role of mitochondrial dysfunction and cardiomyocyte senescence in HHCY-associated myocardial remodeling and to explore the potential protective effects of AP39, a mitochondria-targeted hydrogen sulfide (H2S) donor.
Methods:
An integrated approach combining retrospective clinical analysis, animal models, and cellular experiments was employed. Associations between homocysteine (HCY) levels and left ventricular hypertrophy were analyzed in hypertensive patients. In vivo and in vitro models of HHCY were used to assess cardiac function, myocardial fibrosis, cellular senescence, mitochondrial dynamics, and underlying molecular mechanisms, with or without AP39 intervention.
Results:
Clinical analysis demonstrated that HHCY was significantly associated with left ventricular hypertrophy, and elevated HCY levels increased the risk of ventricular hypertrophy. In animal models, HHCY resulted in impaired cardiac function, evidenced by reduced left ventricular fractional shortening and increased left ventricular end-systolic diameter, accompanied by myocardial fibrosis and cardiomyocyte senescence. AP39 treatment markedly ameliorated these pathological changes. Mechanistically, AP39-derived H2S promoted S-sulfhydration of the NEDD8/CUL4B complex, thereby reducing ubiquitin-dependent degradation of FUNDC1. Upregulation of FUNDC1 restored mitochondrial dynamic homeostasis by weakening its interaction with DRP1, ultimately suppressing cardiomyocyte senescence.
Discussion:
These findings uncover a previously unrecognized mechanism by which AP39 preserves mitochondrial homeostasis through regulation of the FUNDC1-DRP1 axis via NEDD8/CUL4B-dependent S-sulfhydration. This study identifies a novel therapeutic target and provides mechanistic insight into HHCY-associated myocardial remodeling.
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