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Lentinan alleviates diabetic cardiomyopathy by suppressing CAV1/SDHA-regulated mitochondrial dysfunction
Shuiqing Hu1, Jinlan Luo2, Ping Guo1
1Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.
Abstract:
Diabetic cardiomyopathy (DCM), characterized by mitochondrial dysfunction and impaired energetics as contributing factors, significantly contributes to high mortality in patients with diabetes. Targeting key proteins involved in mitochondrial dysfunction might offer new therapeutic possibilities for DCM. Lentinan (LNT), a β-(1,3)-glucan polysaccharide obtained from lentinus edodes, has demonstrated biological activity in modulating metabolic syndrome. In this study, the authors investigate LNT's pharmacological effects on and mechanisms against DCM. The results demonstrate that administering LNT to db/db mice reduces cardiomyocyte apoptosis and mitochondrial dysfunction, thereby preventing DCM. Notably, these effects are fully negated by Caveolin-1 (CAV1) overexpression both in vivo and in vitro. Further studies and bioinformatics analysis uncovered that CAV1 bound with Succinate dehydrogenase subunit A (SDHA), triggering the following ubiquitination and degradation of SDHA, which leads to mitochondrial dysfunction and mitochondria-derived apoptosis under PA condition. Silencing CAV1 leads to reduced apoptosis and improved mitochondrial function, which is blocked by SDHA knockdown. In conclusion, CAV1 directly interacts with SDHA to promote ubiquitination and proteasomal degradation, resulting in mitochondrial dysfunction and mitochondria-derived apoptosis, which was depressed by LNT administration. Therefore, LNT may be a potential pharmacological agent in preventing DCM, and targeting the CAV1/SDHA pathway may be a promising therapeutic approach for DCM.
Insights
Lentinan (LNT) prevents diabetic cardiomyopathy (DCM) by protecting against cardiomyocyte apoptosis and mitochondrial dysfunction. This effect is mediated by the Lentinan
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Pharmacology
Background:
- Diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients, linked to mitochondrial dysfunction and impaired energetics.
- Identifying therapeutic targets within mitochondrial pathways is crucial for managing DCM.
- Lentinan (LNT), a polysaccharide from *Lentinus edodes*, shows potential in metabolic syndrome modulation.
Purpose of the Study:
- To investigate the pharmacological effects and underlying mechanisms of Lentinan (LNT) against diabetic cardiomyopathy (DCM).
- To elucidate the role of Caveolin-1 (CAV1) and Succinate dehydrogenase subunit A (SDHA) in DCM pathogenesis and LNT's action.
Main Methods:
- Administration of LNT to diabetic db/db mice models.
- In vivo and in vitro studies involving CAV1 overexpression and silencing.
- Bioinformatics analysis to identify protein interactions and ubiquitination pathways.
- Assessment of cardiomyocyte apoptosis, mitochondrial function, and SDHA protein levels.
Main Results:
- LNT treatment significantly reduced cardiomyocyte apoptosis and improved mitochondrial function in db/db mice, preventing DCM.
- CAV1 overexpression negated the protective effects of LNT, highlighting its critical role.
- CAV1 was found to bind with SDHA, promoting its ubiquitination and degradation, leading to mitochondrial dysfunction and apoptosis.
- Silencing CAV1 improved mitochondrial function and reduced apoptosis, effects blocked by SDHA knockdown.
Conclusions:
- CAV1 directly interacts with SDHA, leading to SDHA degradation, mitochondrial dysfunction, and apoptosis in DCM.
- LNT administration inhibits the CAV1/SDHA interaction, thereby preventing DCM progression.
- LNT represents a potential therapeutic agent for DCM, and targeting the CAV1/SDHA pathway offers a promising therapeutic strategy.
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