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

Abstract

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.

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

“…Indeed, TGF-β1 has a controversial role in the pathogenesis of ulcerative colitis ( Feagins, 2010 ; Ihara et al, 2017 ), yet it was here part of the pathomechanism. The anti-fibrotic potential of the tested drugs has been reported earlier in non-ulcerative colitis models; first, carvedilol was able to decrease TGF-β1/α-SMA and increase SMAD-7 in renal ( Wong et al, 2001 ) and hepatic ( El-Wakeel et al, 2018 ) injury models, whereas mirabegron proved its anti-fibrotic potential against doxorubicin-induced cardiotoxicity via the inhibition of TGF-β/SMAD2/3 pathway ( Freiwan et al, 2022 ). However, the aptitude of mirabegron to release noradrenaline ( Mo et al, 2017 ) may also be one possible reason behind the augmentation of SMAD-7 ( Kanamaru et al, 2001 ).…”

“…Frontiers in Pharmacology frontiersin.org mirabegron proved its anti-fibrotic potential against doxorubicin-induced cardiotoxicity via the inhibition of TGFβ/SMAD2/3 pathway (Freiwan et al, 2022). However, the aptitude of mirabegron to release noradrenaline (Mo et al, 2017) may also be one possible reason behind the augmentation of SMAD-7 (Kanamaru et al, 2001).…”

Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy

“…Formalin-fixed paraffin-embedded subvalvular areas of the left ventricles and the middle cross-sectional rings of the left kidneys were cut into 5 µm sections and were stained with hematoxylin–eosin (HE) or picrosirius red/fast green (PSFG) as described previously [ 34 , 36 , 43 , 44 ]. Histological slides were scanned with a Pannoramic Midi II scanner (3DHistech Ltd, Budapest, Hungary).…”

“…The Biology Image Analysis Software (BIAS 1.0, Single-Cell Technologies Ltd., Szeged, Hungary, https://single-cell-technologies.com/bias/ ) was used to evaluate HE images [ 34 , 36 , 43 , 44 ]. Image pre-processing was followed by deep learning-based cytoplasm segmentation.…”

Cardiac Fibrosis: Chronic Inflammatory Disease and Promising Therapeutic Target

“…The activation of RAAS is well-known in doxorubicin (Dox)-induced cardiac toxicity. Freiwan et al demonstrated that the simultaneous treatment of angiotensin-II receptor blocker can prevent Dox-induced cardiac diastolic dysfunction and fibrosis in rats [ 4 ]. This was accompanied by the decreased expression in interleukin (IL)-1 and-6.…”