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- Title
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.
- 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
- Abstract
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.
- Subjects
NEPRILYSIN; DOXORUBICIN; HEART diseases; SODIUM-glucose cotransporter 2 inhibitors; ANGIOTENSINS; PEROXISOME proliferator-activated receptors; RODENTS
- Publication
Pharmaceutics, 2022, Vol 14, Issue 12, p2629
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics14122629