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Updated: Apr 16, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways
Yang Ruan1, Chunlin Dong, Jigar Patel
1Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
Background:
SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro.
Methods:
We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.
Results:
SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes.
Conclusions:
These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.
Insights
Sirtuin 1 (SIRT1) protects against doxorubicin-induced heart injury by reducing cardiomyocyte apoptosis and oxidative stress. Overexpressing SIRT1 or using its agonist resveratrol mitigates heart damage, suggesting SIRT1 as a therapeutic target for chemotherapy-induced cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Biochemistry
Background:
- Sirtuin 1 (SIRT1) is an NAD-dependent enzyme involved in aging, metabolism, and disease.
- SIRT1 plays a protective role in cardiac function and cell survival.
- Doxorubicin chemotherapy can induce significant cardiomyocyte injury and heart failure.
Purpose of the Study:
- To investigate the mechanism by which SIRT1 regulates doxorubicin-induced cardiomyocyte injury.
- To evaluate the therapeutic potential of SIRT1 in mitigating doxorubicin cardiotoxicity.
Main Methods:
- Analyzed SIRT1 expression in doxorubicin-induced injury models (neonatal rat cardiomyocytes and adult mouse heart failure).
- Overexpressed SIRT1 using adenovirus-mediated gene transfer in cultured cardiomyocytes.
- Administered SIRT1 agonist resveratrol to a doxorubicin-induced heart failure mouse model.
- Assessed cell survival, oxidative stress (ROS), apoptosis (TUNEL), and inflammatory pathways (qRT-PCR, Western blotting).
Main Results:
- SIRT1 expression decreased in doxorubicin-induced injury, correlating with increased oxidative stress and apoptosis.
- SIRT1 overexpression attenuated doxorubicin-induced cardiomyocyte apoptosis and reduced reactive oxygen species (ROS) production.
- SIRT1 inhibited p38MAPK phosphorylation and caspase-3 activation, thereby reducing apoptosis.
- Resveratrol prevented doxorubicin-induced heart function loss, while the SIRT1 inhibitor niacinamide reversed protective effects.
Conclusions:
- SIRT1 is a key regulator of cardiomyocyte apoptosis in doxorubicin-induced heart injury.
- SIRT1 activation demonstrates a protective effect against doxorubicin cardiotoxicity.
- SIRT1 represents a promising therapeutic target for preventing or treating doxorubicin-induced cardiomyopathy.
