Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

Kovács, Mónika G.; Kovács, Zsuzsanna; Varga, Zoltán; Szűcs, Gergő; Freiwan, Marah; Farkas, Katalin; Kővári, Bence; Kriston, András; Kovács, Ferenc; Horváth, Péter; Földesi, Imre; Csont, Tamás; Kahán, Zsuzsanna; Sárközy, Márta

doi:10.3390/ijms222312963

Cited by 12 publications

(30 citation statements)

References 59 publications

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“…Since our DOXO-induced cardiotoxicity model developed bradycardia, we avoided the administration of beta-blockers alone or in combination with ARBs. The ARB losartan showed antiremodeling and cardioprotective effects in our rat models of radiation-induced heart disease [49] and uremic cardiomyopathy [29], or DOXO-induced chronic cardiotoxicity models used by others [19,50,51]. In contrast, in our hands, losartan failed to significantly improve the morphologic parameters (i.e., systolic wall thicknesses, LV end-systolic diameter, cardiomyocyte cross-sectional area) and the systolic dysfunction (i.e., reduced FS and EF) in DOXO-induced chronic cardiotoxicity in the present study.…”

Section: Discussionmentioning

confidence: 77%

“…Cardiac morphology and function were assessed by transthoracic echocardiography as described previously [49] at weeks 4 and 8 to monitor the development of DOXOinduced chronic cardiotoxicity. Rats were anesthetized with 2% isoflurane (Forane, Aesica, Queenborough Limited, Queenborough, UK).…”

Section: Transthoracic Echocardiographymentioning

confidence: 99%

“…On the digital HE images, cardiomyocyte cross-sectional areas were measured to assess the ventricular wall thinning at the cellular level. For the evaluation, Biology Image Analysis Software (BIAS) was used [29,49]. BIAS (internal built, dated December 2019; https: //single-cell-technologies.com/bias/, accessed on 9 January 2022) is developed by Single-Cell Technologies Ltd., Szeged, Hungary, and the first publicly available version is expected to be released in early 2022.…”

Section: Hematoxylin-eosin and Picrosirius Red And Fast Green Stainingsmentioning

confidence: 99%

“…To investigate gene expression changes at the protein level, a standard Western blot technique was used as described previously [29,49]. TGFβRII (85 kDa) with GAPDH (37 kDa) loading background and SERCA2a (114 kDa), β3AR (44 kDa), eNOS (140 kDa), and p-eNOS (140 kDa) with α-tubulin (52 kDa) loading background were assessed at week 9.…”

Section: Western Blotmentioning

confidence: 99%

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

Freiwan

Kovács

et al. 2022

IJMS

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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.

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Section: Discussionmentioning

confidence: 77%

Section: Transthoracic Echocardiographymentioning

confidence: 99%

Section: Hematoxylin-eosin and Picrosirius Red And Fast Green Stainingsmentioning

confidence: 99%

Section: Western Blotmentioning

confidence: 99%

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

Freiwan

Kovács

et al. 2022

IJMS

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“…One example in particular, the small molecule pharmaceutical losartan, is an FDA-approved angiotensin II receptor antagonist that acts to dampen the downstream effects of the TGFβ pathway, which is a key player in the fibrotic cascade [ 8 ]. Losartan was originally developed as an anti-hypertensive treatment, but has also been demonstrated to elicit antifibrotic effects in the heart [ 9 , 10 ], kidneys [ 11 ], liver [ 12 , 13 ], and skeletal muscle (including rodent models of traumatic muscle injuries) [ 6 , 8 , 14 , 15 ]. The administration of losartan throughout the subacute period (i.e., 14 days) of a VML injury has been demonstrated to reduce fibrosis in a preclinical rodent model by day 28 post-injury [ 6 ]; however, the potential benefit of its chronic delivery (≥56 days) has yet to be established.…”

Section: Introductionmentioning

confidence: 99%

Effects of Adjunct Antifibrotic Treatment within a Regenerative Rehabilitation Paradigm for Volumetric Muscle Loss

Motherwell

Dolan

Kanovka

et al. 2023

IJMS

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The use of a rehabilitation approach that promotes regeneration has the potential to improve the efficacy of pro-regenerative therapies and maximize functional outcomes in the treatment of volumetric muscle loss (VML). An adjunct antifibrotic treatment could further enhance functional gains by reducing fibrotic scarring. This study aimed to evaluate the potential synergistic effects of losartan, an antifibrotic pharmaceutical, paired with a voluntary wheel running rehabilitation strategy to enhance a minced muscle graft (MMG) pro-regenerative therapy in a rodent model of VML. The animals were randomly assigned into four groups: (1) antifibrotic with rehabilitation, (2) antifibrotic without rehabilitation, (3) vehicle treatment with rehabilitation, and (4) vehicle treatment without rehabilitation. At 56 days, the neuromuscular function was assessed, and muscles were collected for histological and molecular analysis. Surprisingly, we found that the losartan treatment decreased muscle function in MMG-treated VML injuries by 56 days, while the voluntary wheel running elicited no effect. Histologic and molecular analysis revealed that losartan treatment did not reduce fibrosis. These findings suggest that losartan treatment as an adjunct therapy to a regenerative rehabilitation strategy negatively impacts muscular function and fails to promote myogenesis following VML injury. There still remains a clinical need to develop a regenerative rehabilitation treatment strategy for traumatic skeletal muscle injuries. Future studies should consider optimizing the timing and duration of adjunct antifibrotic treatments to maximize functional outcomes in VML injuries.

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

Dinh,

Kovács,

Kis

et al. 2023

GeroScience

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The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction’s echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13’s influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.

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Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

Cited by 12 publications

References 59 publications

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

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

Effects of Adjunct Antifibrotic Treatment within a Regenerative Rehabilitation Paradigm for Volumetric Muscle Loss

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

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