ISSN: 1449-1907International Journal of Medical Sciences
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Int J Med Sci 2024; 21(3):439-453. doi:10.7150/ijms.88134 This issue Cite
Research Paper
Deficiency of diacylglycerol Kinase ζ promotes Beclin1-mediated autophagy via the mTOR/TFEB signaling pathway: Relevance to maladaptive cardiac hypertrophy
1. Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, P.R. China.
2. Department of Pharmacology, Jiaying University, Meizhou, 514000, P.R. China.
3. Department of Stomatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
4. Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, 361005, P.R. China.
5. Affiliated Guangxi International Zhuang Medical Hospital, Guangxi University of Traditional Chinese Medicine, Guangxi, 530021, P.R. China.
6. Nanhai Mental Health Center, People's Hospital of Nanhai District, Foshan, 528200, P.R. China.
7. Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
* Yumei Liu, Han Zhang and Yaxian Lin contributed equally to this work
Abstract
The activation Gq protein-coupled receptors (GPCRs) is a crucial factor contributing to maladaptive cardiac hypertrophy, and dysregulation of autophagy is implicated in its prohypertrophic effects. Previous studies have shown that diacylglycerol kinase zeta (DGKζ) can suppress cardiac hypertrophy by inhibiting the diacylglycerol (DAG)-PKC pathway in response to mechanical strain or growth agonists such as endothelin-1 (ET-1). However, the involvement of DGKζ in autophagy regulation remains poorly understood. In this study, we aimed to investigate the role of DGKζ in autophagy regulation during maladaptive cardiac hypertrophy. We found that Beclin1-mediated autophagy was involved in the development of maladaptive cardiac hypertrophy and dysfunction in response to prohypertrophic challenges of transverse aortic constriction (TAC) or ET-1. Deficiency of DGKζ promoted Beclin1-mediated autophagy, aggravated adverse cardiac remodeling, and cardiac dysfunction, which could be ameliorated by genetic deletion of Beclin1 or TFEB. Mechanistically, the deficiency of DGKζ disrupted the activation of AKT/mTOR signaling, the association between mTOR and TFEB, and favored the nuclear translocation of TFEB from the cytoplasm, leading to enhanced activation of Beclin1-mediated autophagy through ULK1/Beclin1 signaling and TFEB-dependent Beclin1 transcription. Taken together, these results suggest that the mechanisms by which DGKζ alleviates pathological cardiac hypertrophy may involve the regulation of Beclin1-mediated autophagy through the mTOR/TFEB signaling pathway.
Keywords: Autophagy, DGKζ, TFEB, Cardiac hypertrophy
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