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Updated: Jul 1, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Diazoxide attenuates DOX-induced cardiotoxicity in cultured rat myocytes
Celal Guven1, Eylem Taskin2, Özgül Aydın3
1Department of Biophysics, Faculty of Medicine, Adıyaman University, Adıyaman, Turkey.
Abstract:
Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy.
Insights
Diazoxide (DIA) protects against doxorubicin (DOX)-induced cardiotoxicity by preserving mitochondrial function and reducing oxidative stress. This study suggests DIA may be a potential therapeutic agent to prevent chemotherapy-related heart damage.
Area of Science:
- Cardiology
- Pharmacology
- Cell Biology
Background:
- Doxorubicin (DOX) chemotherapy can cause cardiotoxicity, leading to myocardial cell loss.
- Mitochondrial ATP-sensitive potassium channels (mitoKATP) are implicated in cellular protection.
- Diazoxide (DIA) is a known mitoKATP channel opener.
Purpose of the Study:
- To investigate the protective effects of diazoxide (DIA) against doxorubicin (DOX)-induced cardiotoxicity in cultured rat cardiomyocytes.
- To explore the role of specific proteins and pathways, including mitochondrial function and oxidative stress markers, in this protective mechanism.
Main Methods:
- Cultured rat cardiomyocytes (H9c2 cell line) were treated with DOX alone or co-treated with DOX and DIA for 24 hours.
- Assessed parameters included actin filament distribution, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant/antioxidant status (TOS/TAS), and protein expression (ERK1/2, cytochrome c).
Main Results:
- DOX treatment decreased SOD activity, increased ERK1/2 levels, and depolarized mitochondrial membranes.
- DIA co-treatment counteracted these effects, preserving SOD activity and mitochondrial potential.
- DIA ameliorated DOX-induced cytoskeletal damage, reduced ERK1/2 and cytochrome c levels, and enhanced mitoKATP integrity, particularly with elevated SUR2A.
Conclusions:
- Diazoxide (DIA) demonstrates protective effects against doxorubicin (DOX)-induced cardiotoxicity.
- The protective mechanism involves maintaining mitoKATP channel integrity and modulating the SOD/AMPK/ERK1/2 pathway.
- DIA is a potential candidate for preventing chemotherapy-induced heart damage.
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