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Updated: Jul 2, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
SIRT6 activates PPARα to improve doxorubicin-induced myocardial cell aging and damage
Shulin Wang1, Xuan Zhang2, Yanhong Hou2
1The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou, China.
Abstract:
The Sirtuins family, formally known as the Silent Information Regulator Factors, constitutes a highly conserved group of histone deacetylases. Recent studies have illuminated SIRT6's role in doxorubicin (DOX)-induced oxidative stress and apoptosis within myocardial cells. Nevertheless, the extent of SIRT6's impact on DOX-triggered myocardial cell aging and damage remains uncertain, with the associated mechanisms yet to be fully understood. In our research, we examined the influence of SIRT6 on DOX-induced cardiomyocyte senescence using β-galactosidase and γ-H2AX staining. Additionally, we gauged the mRNA expression of senescence-associated genes, namely p16, p21, and p53, through Real-time PCR. Employing ELISA assay kits, MDA, and total SOD activity assay kits, we measured inflammatory factors TNF-α, IL-6, and IL-1β, alongside oxidative stress-related indicators. The results unequivocally indicated that SIRT6 overexpression robustly inhibited DOX-induced cardiomyocyte senescence. Furthermore, we established that SIRT6 overexpression suppressed the inflammatory response and oxidative stress induced by DOX in cardiomyocytes. Conversely, silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury. Our investigations further unveiled that SIRT6 upregulated the expression of genes CD36, CPT1, LCAD, MCAD associated with fatty acid oxidation through its interaction with PPARα, thereby exerting anti-aging effects. In vivo, the overexpression of SIRT6 was observed to restore DOX-induced declines in EF and FS to normal levels in mice. Echocardiography and HE staining revealed the restoration of cardiomyocyte alignment, affording protection against DOX-induced myocardial senescence and injury. The findings from this study suggest that SIRT6 holds significant promise as a therapeutic target for mitigating DOX-induced cardiomyopathy.
Insights
SIRT6 overexpression protects against doxorubicin-induced heart cell aging and damage by reducing inflammation and oxidative stress. This finding suggests SIRT6 as a potential therapeutic target for doxorubicin-induced cardiomyopathy.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Cellular Aging
Background:
- Sirtuins (Silent Information Regulator Factors) are conserved histone deacetylases.
- SIRT6 is implicated in doxorubicin (DOX)-induced myocardial oxidative stress and apoptosis.
- The precise role of SIRT6 in DOX-induced cardiomyocyte aging and damage requires further elucidation.
Purpose of the Study:
- To investigate the role of SIRT6 in doxorubicin-induced cardiomyocyte senescence and injury.
- To explore the underlying mechanisms by which SIRT6 influences DOX-triggered cardiac damage.
- To evaluate the therapeutic potential of SIRT6 in mitigating DOX-induced cardiomyopathy.
Main Methods:
- Assessed cardiomyocyte senescence using β-galactosidase and γ-H2AX staining.
- Quantified senescence-associated gene expression (p16, p21, p53) via Real-time PCR.
- Measured inflammatory cytokines (TNF-α, IL-6, IL-1β) and oxidative stress markers (MDA, SOD) using ELISA and assay kits.
- Analyzed fatty acid oxidation-related gene expression (CD36, CPT1, LCAD, MCAD) and PPARα interaction.
- Evaluated cardiac function (EF, FS) and cardiomyocyte structure in vivo using echocardiography and HE staining.
Main Results:
- SIRT6 overexpression significantly inhibited DOX-induced cardiomyocyte senescence, inflammation, and oxidative stress.
- Silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury.
- SIRT6 upregulated fatty acid oxidation genes (CD36, CPT1, LCAD, MCAD) via PPARα interaction, conferring anti-aging effects.
- In vivo, SIRT6 overexpression restored cardiac function (EF, FS) and cardiomyocyte alignment in DOX-treated mice.
Conclusions:
- SIRT6 overexpression protects against DOX-induced myocardial senescence and injury.
- SIRT6 exerts cardioprotective effects by suppressing inflammation, oxidative stress, and promoting fatty acid oxidation.
- SIRT6 represents a promising therapeutic target for preventing and treating doxorubicin-induced cardiomyopathy.
