Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model

• Published in: International journal of molecular sciences 2022-02, Vol.23 (4), p.2201
• Main Authors: Freiwan, Marah, Kovács, Mónika G, Kovács, Zsuzsanna Z A, Szűcs, Gergő, Dinh, Hoa, Losonczi, Réka, Siska, Andrea, Kriston, András, Kovács, Ferenc, Horváth, Péter, Földesi, Imre, Cserni, Gábor, Dux, László, Csont, Tamás, Sárközy, Márta
• Format: Article
• Language: English
• Subjects: Acetanilides; Adrenergic receptors; Angiotensin; Angiotensin II; Animal models; Animals; Apoptosis; Blood pressure; Ca2+-transporting ATPase; Cancer therapies; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiotoxicity; Cardiotoxicity - drug therapy; Cardiotoxicity - etiology; Cardiovascular disease; Cholesterol; Clinical trials; Congestive heart failure; Deoxyribonucleic acid; DNA; Doxorubicin; Doxorubicin - adverse effects; Drug dosages; Echocardiography; Ejection fraction; Etiology; Fibrosis; Heart failure; Histology; Hypertension; Interleukin 1; Interleukin 6; Losartan - adverse effects; Male; Mortality; Oxidative stress; Rats; Rats, Wistar; Receptors (physiology); Smad2 protein; Smad3 protein; Thiazoles
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042201

Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of and was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of 2 and in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.