Combined Therapy of Low-Dose Angiotensin Receptor-Neprilysin Inhibitor and Sodium-Glucose Cotransporter-2 Inhibitor Prevents Doxorubicin-Induced Cardiac Dysfunction in Rodent Model with Minimal Adverse Effects

Combined Therapy of Low-Dose Angiotensin Receptor-Neprilysin Inhibitor and Sodium-Glucose Cotransporter-2 Inhibitor Prevents Doxorubicin-Induced Cardiac Dysfunction in Rodent Model with Minimal Adverse Effects

Although cancer-therapy-related cardiac dysfunction (CTRCD) is a critical issue in clinical practice, there is a glaring lack of evidence regarding cardiotoxicity management. To determine an effective and suitable dosage of treatment using angiotensin receptor-neprilysin inhibitors (ARNI) with sodiu...

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Bibliographic Details
Published in:Pharmaceutics Vol. 14; no. 12; p. 2629
Main Authors: Kim, Donghyun, Jang, Gyuho, Hwang, Jaetaek, Wei, Xiaofan, Kim, Hyunsoo, Son, Jinbae, Rhee, Sang-Jae, Yun, Kyeong-Ho, Oh, Seok-Kyu, Oh, Chang-Myung, Park, Raekil
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 28-11-2022
MDPI
Subjects:
Angiotensin II receptor blockers
angiotensin receptor–neprilysin inhibitor
Antimitotic agents
Antineoplastic agents
Blood pressure
Cancer
Cardiac function
Cardiotoxicity
Care and treatment
Complications and side effects
Dosage and administration
doxorubicin
Drug dosages
Ejection fraction
Glucose
Heart diseases
Heart failure
Hypoglycemic agents
Peptides
peroxisome proliferator-activated receptors
Prevention
Proteins
sodium–glucose cotransporter 2 inhibitor
Testing
South Korea
Minneapolis Minnesota
United Kingdom > UK
United States > US
Basel Switzerland
Ann Arbor Michigan
Switzerland
Germany
angiotensin receptor–neprilysin inhibitor
heart failure
sodium–glucose cotransporter 2 inhibitor
doxorubicin
peroxisome proliferator-activated receptors
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Summary:Although cancer-therapy-related cardiac dysfunction (CTRCD) is a critical issue in clinical practice, there is a glaring lack of evidence regarding cardiotoxicity management. To determine an effective and suitable dosage of treatment using angiotensin receptor-neprilysin inhibitors (ARNI) with sodium-glucose cotransporter 2 inhibitors (SGLT2i), we adopted a clinically relevant rodent model with doxorubicin, which would mimic cardiac dysfunction in CTRCD patients. After the oral administration of drugs (vehicle, SGLT2i, ARNI, Low-ARNI/SGLT2i, ARNI/SGLT2i), several physiologic parameters, including hemodynamic change, cardiac function, and histopathology, were evaluated. Bulk RNA-sequencing was performed to obtain insights into the molecular basis of a mouse heart response to Low-ARNI/SGLT2i treatment. For the first time, we report that the addition of low-dose ARNI with SGLT2i resulted in greater benefits than ARNI, SGLT2i alone or ARNI/SGLT2i combination in survival rate, cardiac function, hemodynamic change, and kidney function against doxorubicin-induced cardiotoxicity through peroxisome proliferator-activated receptor signaling pathway. Low-dose ARNI with SGLT2i combination treatment would be practically beneficial for improving cardiac functions against doxorubicin-induced heart failure with minimal adverse effects. Our findings suggest the Low-ARNI/SGLT2i combination as a feasible novel strategy in managing CTRCD patients.
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ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14122629