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Baicalin Attenuates Diabetic Cardiomyopathy In Vivo and In Vitro by Inhibiting Autophagy and Cell Death Through
Peipei Zhang1, Haowei Wu2, Haifei Lou1
1School of Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
Insights
Baicalin (BAI) protects against diabetic heart damage by enhancing Sirtuin 3 (SIRT3) deSUMOylation via SENP1, improving mitochondrial function and preventing cardiomyocyte death in diabetic cardiomyopathy (DCM).
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Molecular Medicine
Background:
- Diabetic cardiomyopathy (DCM) involves cardiomyocyte death, significantly impacting health.
- Baicalin (BAI) is a bioactive compound with known cardiovascular benefits.
- Sentrin/SUMO-specific protease 1 (SENP1) regulates Sirtuin 3 (SIRT3) deSUMOylation, crucial for mitochondrial quality control and cell protection.
Purpose of the Study:
- To investigate if BAI enhances mitochondrial quality control and prevents cell death in DCM by modulating SIRT3 deSUMOylation through SENP1.
- To elucidate the molecular mechanisms underlying BAI's cardioprotective effects in the context of DCM.
Main Methods:
- Utilized high glucose-induced cardiomyocytes and db/db mice models.
- Performed gene silencing and overexpression of SENP1.
- Employed co-immunoprecipitation to assess SIRT3 SUMOylation levels.
- Analyzed mitochondrial protein acetylation, reactive oxygen species accumulation, autophagy, oxidative phosphorylation, and cell death.
Main Results:
- SENP1 expression was reduced in high glucose-induced cardiomyocytes and db/db mice.
- Silencing SENP1 abolished BAI's cardioprotective effects, while SENP1 overexpression mimicked them.
- BAI inhibited SIRT3 SUMOylation via SENP1, preventing mitochondrial dysfunction and cell death.
- Inhibition of SENP1 led to increased SIRT3 SUMOylation, mitochondrial damage, and cell death, which BAI could not reverse.
Conclusions:
- BAI improves DCM by promoting SIRT3 deSUMOylation through SENP1, thereby restoring mitochondrial stability and preventing cardiomyocyte death.
- This study identifies SIRT3 SUMOylation as a key factor in DCM development.
- BAI demonstrates cardioprotective effects against ferroptosis and apoptosis in DCM by targeting the SENP1 pathway.
Abstract:
Aims: Diabetic heart damage can lead to cardiomyocyte death, which endangers human health. Baicalin (BAI) is a bioactive compound that plays an important role in cardiovascular diseases. Sentrin/SUMO-specific protease 1 (SENP1) regulates the de-small ubiquitin-like modifier (deSUMOylation) process of Sirtuin 3 (SIRT3) and plays a crucial role in regulating mitochondrial mass and preventing cell injury. Our hypothesis is that BAI regulates the deSUMOylation level of SIRT3 through SENP1 to enhance mitochondrial quality control and prevent cell death, ultimately improving diabetic cardiomyopathy (DCM). Results: The protein expression of SENP1 decreased in cardiomyocytes induced by high glucose and in db/db mice. The cardioprotective effects of BAI were eliminated by silencing endogenous SENP1, whereas overexpression of SENP1 showed similar cardioprotective effects to those of BAI. Furthermore, co-immunoprecipitation experiments showed that BAI's cardioprotective effect was due to the inhibition of the SUMOylation modification level of SIRT3 by SENP1. Inhibition of SENP1 expression resulted in an increase in SUMOylation of SIRT3. This led to increased acetylation of mitochondrial protein, accumulation of reactive oxygen species, impaired autophagy, impaired mitochondrial oxidative phosphorylation, and increased cell death. None of these changes could be reversed by BAI. Conclusion: BAI improves DCM by promoting SIRT3 deSUMOylation through SENP1, restoring mitochondrial stability, and preventing the cell death of cardiomyocytes. Innovation: This study proposes for the first time that SIRT3 SUMOylation modification is involved in the development of DCM and provides in vivo and in vitro data support that BAI inhibits cardiomyocyte ferroptosis and apoptosis in DCM through SENP1. Antioxid. Redox Signal. 42, 53-76.
