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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
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The Mechanisms of Cardiac Protection Using a Synthetic Agonist of Galanin Receptors during Chronic Administration of
I M Studneva1, O M Veselova1, A A Bahtin2
1National Medical Research Center for Cardiology, Moscow, 121552 Russia.
Abstract:
The use of the anticancer drug doxorubicin (Dox) is limited by its cardiotoxic effect. The aim of this work was to study the effect of a new synthetic agonist of the galanin receptor GalR1-3 [βAla14, His15]-galanine (2-15) (G) on the metabolism, antioxidant enzyme activity, and cardiac function in rats with cardiomyopathy (CM) caused by chronic administration of Dox. Coadministration of peptide G and Dox significantly increased the fractional shortening (FS) and ejection fraction (EF) by an average of 30 ± 4% compared with the indices in the Dox group. The reduced severity of cardiac dysfunction under the action of G was accompanied by a 2.5-fold decrease in the activity of creatine kinase-MB (CK-MB) in blood plasma. The protective mechanism of the action of peptide G is caused by a reduced lipid peroxidation (LP) that is due to the increased activity of Cu,Zn superoxide dismutase (Cu,Zn-SOD) and glutathione peroxidase (GSH-Px) in the damaged heart. Administration of peptide G significantly increased the adenine nucleotide pool (ΣAH), ATP content, and the levels of phosphocreatine (PCr) and total creatine (ΣCr) in the damaged myocardium. It also reduced lactate accumulation relative to its content in the Dox group. The better energy supply of cardiomyocytes after treatment with peptide G prevented the accumulation of cytotoxic ammonia and disruption in the metabolism of the key myocardial amino acids (glutamic acid (Glu), aspartic acid (Asp), and alanine (Ala)). Peptide G significantly improved the morphological parameters of the heart in rats treated with Dox. The results show promise in using peptide G to efficiently correct functional, morphological, and metabolic damage to the heart caused by anthracycline chemotherapy.
Insights
A new peptide agonist of galanin receptors protected rat hearts from doxorubicin-induced cardiotoxicity by improving cardiac function, antioxidant activity, and energy metabolism, offering a potential therapeutic strategy.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Doxorubicin (Dox) chemotherapy causes cardiotoxicity, limiting its clinical use.
- Cardiomyopathy (CM) induced by Dox negatively impacts cardiac function and metabolism.
- Galanin receptor agonists represent a potential therapeutic avenue for mitigating Dox-induced cardiac damage.
Purpose of the Study:
- To investigate the protective effects of a novel synthetic galanin receptor agonist, [βAla14, His15]-galanine (2-15) (G), on Dox-induced cardiotoxicity in rats.
- To evaluate the impact of peptide G on cardiac metabolism, antioxidant enzyme activity, and cardiac function in a rat model of Dox-induced CM.
- To elucidate the underlying mechanisms of peptide G's cardioprotective action.
Main Methods:
- Induction of cardiomyopathy in rats through chronic doxorubicin administration.
- Coadministration of doxorubicin with peptide G.
- Assessment of cardiac function using fractional shortening (FS) and ejection fraction (EF).
- Measurement of cardiac enzyme activity (CK-MB), lipid peroxidation (LP), and antioxidant enzyme activity (Cu,Zn-SOD, GSH-Px).
- Analysis of myocardial energy metabolism, including adenine nucleotide pool (ΣAH), ATP, phosphocreatine (PCr), total creatine (ΣCr), and lactate levels.
- Evaluation of myocardial amino acid metabolism and morphological parameters.
Main Results:
- Coadministration of peptide G with doxorubicin significantly improved fractional shortening (FS) and ejection fraction (EF) by approximately 30%.
- Peptide G reduced cardiac dysfunction markers, evidenced by a 2.5-fold decrease in creatine kinase-MB (CK-MB) activity.
- The protective effects were associated with reduced lipid peroxidation (LP) and increased activity of antioxidant enzymes (Cu,Zn-SOD and GSH-Px).
- Peptide G administration enhanced myocardial energy status by increasing the adenine nucleotide pool (ΣAH), ATP, phosphocreatine (PCr), and total creatine (ΣCr), while reducing lactate accumulation.
- Improved energy supply prevented ammonia accumulation and normalized key myocardial amino acid metabolism, alongside significant improvements in cardiac morphology.
Conclusions:
- The synthetic galanin receptor agonist peptide G demonstrates significant cardioprotective effects against doxorubicin-induced cardiotoxicity in rats.
- Peptide G improves cardiac function, reduces oxidative stress, and enhances myocardial energy metabolism.
- These findings suggest that peptide G holds promise for preventing or treating heart damage associated with anthracycline chemotherapy.
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