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Published on: June 3, 2018
Overexpression of ATP5F1A in Cardiomyocytes Promotes Cardiac Reverse Remodeling
Mengda Xu1, Hang Zhang1, Yuan Chang1
1Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, China. Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China. The Cardiomyopathy Research Group at Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, China.
Background:
The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR.
Methods:
The nuclei were extracted from the left ventricular tissue of 4 normal controls, 4 CRR patients, and 4 no cardiac reverse remodeling patients and then subjected to single-nucleus RNA sequencing for identifying key cell types responsible for CRR. Gene overexpression in transverse aortic constriction and dilated cardiomyopathy heart failure mouse model (C57BL/6J background) and pathological staining were performed to validate the results of single-nucleus RNA sequencing.
Results:
Ten cell types were identified among 126 156 nuclei. Cardiomyocytes in CRR patients expressed higher levels of ATP5F1A than the other 2 groups. The macrophages in CRR patients expressed more anti-inflammatory genes and functioned in angiogenesis. Endothelial cells that elevated in no cardiac reverse remodeling patients were involved in the inflammatory response. Echocardiography showed that overexpressing ATP5F1A through cardiomyocyte-specific adeno-associated virus 9 demonstrated an ability to improve heart function and morphology. Pathological staining showed that overexpressing ATP5F1A could reduce fibrosis and cardiomyocyte size in the heart failure mouse model.
Conclusions:
The present results of single-nucleus RNA sequencing and heart failure mouse model indicated that ATP5F1A could mediate CRR and supported the development of therapeutics for overexpressing ATP5F1A in promoting CRR.
Insights
This study identifies ATP5F1A as a key factor in cardiac reverse remodeling (CRR). Overexpressing ATP5F1A in cardiomyocytes shows potential for developing new therapies to improve heart function in heart failure patients.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Regenerative Medicine
Background:
- The precise mechanisms driving cardiac reverse remodeling (CRR) after left ventricular assist device (LVAD) implantation are not fully understood.
- Identifying the specific cellular players and molecular targets involved in CRR is crucial for developing effective treatments.
Purpose of the Study:
- To pinpoint the cell types responsible for CRR.
- To identify a therapeutic target that can promote CRR.
Main Methods:
- Single-nucleus RNA sequencing was performed on left ventricular tissue from normal controls, CRR patients, and patients without CRR.
- Gene overexpression studies were conducted in a heart failure mouse model (transverse aortic constriction and dilated cardiomyopathy).
- Pathological staining and echocardiography were used for validation.
Main Results:
- Ten distinct cell types were identified. Cardiomyocytes in CRR patients showed elevated ATP5F1A expression.
- Macrophages in CRR patients exhibited anti-inflammatory and pro-angiogenic gene expression.
- Overexpression of ATP5F1A in cardiomyocytes improved cardiac function and morphology, and reduced fibrosis in a mouse model.
Conclusions:
- Single-nucleus RNA sequencing and in vivo mouse models suggest ATP5F1A plays a critical role in mediating CRR.
- Targeting ATP5F1A for overexpression presents a promising therapeutic strategy for promoting CRR and treating heart failure.
