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MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice
Mingming Zhang1,2, Lei Zhang3, Jianqiang Hu1,2
1Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China.
Aims/Hypothesis:
Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM.
Methods:
Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms.
Results:
Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax.
Conclusions/Interpretation:
Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.
Insights
Mammalian sterile 20-like kinase 1 (Mst1) knockout improves autophagy and reduces apoptosis in diabetic cardiomyopathy. Mst1 deficiency protects the heart in diabetes by restoring cardiac function.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Metabolic Diseases
Background:
- Diabetic cardiomyopathy (DCM) involves impaired autophagy and increased apoptosis.
- The precise interplay between autophagy and apoptosis in DCM is not fully understood.
Purpose of the Study:
- To investigate the role of mammalian sterile 20-like kinase 1 (Mst1) in regulating autophagy and apoptosis in DCM.
- To explore Mst1 as a potential therapeutic target for DCM.
Main Methods:
- Induction of experimental diabetes in wild-type, Mst1 transgenic, and Mst1-knockout mice using streptozotocin.
- In vitro simulation of diabetes in cultured neonatal mouse cardiomyocytes.
- Assessment of autophagy markers (LC3, p62), apoptosis, protein aggregation, and protein-protein interactions (Mst1, Beclin1, Bcl-2, Bax).
Main Results:
- Mst1 knockout alleviated cardiac dysfunction and apoptosis in diabetic mice, while Mst1 overexpression aggravated these conditions.
- Mst1 deficiency enhanced autophagic flux and reduced protein aggregation in cardiomyocytes.
- Mst1 modulated the interaction between Beclin1, Bcl-2, and Bax, impacting apoptosis.
Conclusions:
- Mst1 knockout restores cardiac autophagy and protects against apoptosis in DCM.
- Targeting Mst1 may offer a therapeutic strategy for managing diabetic cardiomyopathy.
