Investigation of the antiremodeling effects of losartan, mirabegron and their combination on the development of doxorubicin-induced chronic cardiotoxicity in a rat model

Freiwan Marah
Investigation of the antiremodeling effects of losartan, mirabegron and their combination on the development of doxorubicin-induced chronic cardiotoxicity in a rat model.
Doctoral thesis (PhD), University of Szeged.
(2022)

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Abstract in foreign language

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 Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 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.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Freiwan Marah
Supervisor(s):
Supervisor
Position, academic title, institution
MTMT author ID
Sárközy Márta
MD PhD, Biokémiai Intézet SZTE / SZAOK
10028929
László Dux
MD PhD DSc, Biokémiai Intézet SZTE / SZAOK
10002420
Subjects: 03. Medical and health sciences
Divisions: Doctoral School of Multidisciplinary Medical Sciences
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2022. May 16.
Uncontrolled Keywords: onco-cardiology; doxorubicin-induced chronic cardiotoxicity; heart failure; cardiac fibrosis; diastolic dysfunction; angiotensin II receptor blocker; beta-3 adrenoceptor agonist; cardiac inflammation; TGF-β/SMAD signaling pathway; sarcoendoplasmic reticulum calcium ATPase 2a
Item ID: 11246
MTMT identifier of the thesis: 33094425
doi: https://doi.org/10.14232/phd.11246
Date Deposited: 2022. Mar. 30. 15:37
Last Modified: 2023. Jan. 12. 15:15
URI: https://doktori.bibl.u-szeged.hu/id/eprint/11246
Defence/Citable status: Defended.

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