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

Mónika Gabriella Kovács, Zsuzsanna Z A Kovács, Zoltán Varga, Gergő Szűcs, Marah Freiwan, Katalin Farkas, Bence Kővári, Gábor Cserni, András Kriston, Ferenc Kovács, Péter Horváth, Imre Földesi, Tamás Csont, Zsuzsanna Kahán, Márta Sárközy, Mónika Gabriella Kovács, Zsuzsanna Z A Kovács, Zoltán Varga, Gergő Szűcs, Marah Freiwan, Katalin Farkas, Bence Kővári, Gábor Cserni, András Kriston, Ferenc Kovács, Péter Horváth, Imre Földesi, Tamás Csont, Zsuzsanna Kahán, Márta Sárközy

Abstract

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

Keywords: TGF-β/SMAD signaling pathway; angiotensin-II receptor blocker (ARB); chymase; diastolic dysfunction; fibrosis; heart failure; left ventricular hypertrophy; losartan; onco-cardiology; radiation-induced heart disease.

Conflict of interest statement

Single-Cell Technologies Ltd., Szeged, Hungary, developed the Biology Image Analysis Software (BIAS). P.H. is the CEO, A.K. is a software architect, and F.K. is a software engineer at Single-Cell Technologies Ltd, Szeged, Hungary.

Figures

Figure 1
Figure 1
Experimental setup. Rats (n = 63) were divided into three groups (n = 6–9) and treated via oral gavage daily for 1, 3, or 15 weeks, respectively, as follows: (i) control group treated with tap water, (ii) radiotherapy (RT) only group treated with tap water, and (iii) RT plus losartan group treated with losartan (per os 10 mg/kg/day) dissolved in tap water. Cardiac morphology and function were assessed by transthoracic echocardiography (echo) at the end-points of each experiment under anesthesia. Then, blood was collected from the abdominal aorta to measure routine laboratory parameters, and hearts, lungs, and tibias were isolated. Left and right ventricles were separated, and left ventricular samples were prepared for histology (histo) and biochemical measurements (biochem). The development of LVH and fibrosis in the irradiated groups were investigated by the measurement of cardiomyocyte cross-sectional areas on hematoxylin-eosin-stained slides and picrosirius red/fast green-stained slides. The expression of selected genes related to LVH and fibrosis, heart failure, renin-angiotensin-aldosterone system (RAAS), and inflammation were measured at the transcript level by qRT-PCR. Left ventricular levels of selected proteins related to the RAAS, cardiac hypertrophy, and fibrosis pathways were measured by Western blot.
Figure 2
Figure 2
The effects of losartan on the echocardiographic parameters at weeks 1, 3, and 15. (a) Representative tissue Doppler images of diastolic septal mitral annulus velocity e’, (b) mitral valve early flow velocity (E)/ e’, (c) heart rate, (d) representative M-mode images of wall thicknesses and left ventricular diameters, (e) posterior wall thicknesses in systole (PWTs) and (f) diastole (PWTd). Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, # p < 0.05 vs. RT only group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group. Representative M-mode images were saved from the Echo- Pac Dimension v201 software.
Figure 3
Figure 3
The effects of losartan on left ventricular hypertrophy assessed by histology at weeks 1, 3, and 15. (a) Representative hematoxylin-eosin (HE)-stained sections at 40× and 100× magnification, (b) cardiomyocyte cross-sectional area, (c) alpha-myosin heavy chain (Myh6), and (d) beta-myosin heavy chain (Myh7) expression in the left ventricle normalized to the ribosomal protein lateral stalk subunit P2 (RpIp2) gene expression, (e) Myh7/Myh6 ratios. On the digital HE images, cardiomyocyte (CM) cross-sectional areas were measured in 100 selected cardiomyocytes in left ventricular tissue sections cut on equivalent planes. Scale bars represent 50 µm in the 40× magnified images and 20 µm in the 100× magnified images. Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group. Representative HE-stained slides were captured in the Panoramic Viewer 1.15.4 software.
Figure 4
Figure 4
The effects of losartan on left ventricular fibrosis as assessed by histology and qRT-PCR at weeks 1, 3, and 15. (a) Representative picrosirius red and fast green (PSFG)-stained sections at 20× magnification, (b) left ventricular collagen content, left ventricular expression of (c) connective tissue growth factor (Ctgf), (d) collagen 1a1 (Col1a1) normalized to ribosomal protein lateral stalk subunit P2 (Rplp2) gene expression. The mean values of the collagen content of 10 representative PSFG-stained images were calculated and used for statistical evaluation in each left ventricular sample. Scale bars represent 100 µm at the 20× magnified images. Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, # p < 0.05 vs. RT only group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group. Representative PSFG-stained slides were captured in the Panoramic Viewer 1.15.4 software.2.7.
Figure 5
Figure 5
The effects of losartan on inflammatory gene expressions assessed by qRT-PCR at weeks 1, 3, and 15. Expression of (a) interleukin-1 (Il1), (b) interleukin-6 (Il6), (c) tumor necrosis factor-alpha (Tnfα), (d) matrix metalloprotease-2 (Mmp2), and (e) chymase (Cma) normalized to ribosomal protein lateral stalk subunit P2 (RpIp2) gene expression were measured in left ventricle samples. Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, # p < 0.05 vs. RT only group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group.
Figure 6
Figure 6
The effects of losartan on the expression of genes and proteins related to the cardiac renin-angiotensin-aldosterone system and canonical SMAD-dependent pathway at weeks 1, 3, and 15. Left ventricular expression of (a) angiotensinogen (Agt) normalized to ribosomal protein lateral stalk subunit P2 (RpIp2) gene expression, left ventricular protein expression and cropped representative images of (b) angiotensin II type 1 receptor (AT1R, 41 kDa), and (c) angiotensin II type 2 receptor (AT2R, 41 kDa), (d) left ventricular expression of transforming growth factor-beta (Tgfb) normalized to RpIp2 gene expression, left ventricular expression and cropped representative images of (e) TGF-β receptor II (TGF-βRII, 85 kDa) and (f) SMAD2/3 (52 and 60 kDa). Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, # p < 0.05 vs. RT only group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, 37 kDa) was used as a loading control in protein expression changes assessed by Western blot. Images were captured with the Odyssey CLx machine and exported with Image Studio 5.2.5 software. Black lines next to the Western blot images represent the position of protein markers with corresponding molecular weights. The uncropped Ponceau-stained membranes and the full-length Western blot images with the protein ladders are presented in Figures S1–S9.
Figure 7
Figure 7
The effects of losartan on the expression of proteins associated with the non-canonical SMAD-independent fibrotic pathway at weeks 1, 3, and 15. Left ventricular expression and cropped representative images of (a) phospho-ERK1/total-ERK1 ratio (pERK1/tERK1 42 and 44 kDa), (b) phospho-ERK2/total-ERK2 ratio (pERK2/tERK2, 42 and 44 kDa), (c) phospho-AKT/total-AKT ratio (pAKT/tAKT, 60 kDa), (d) phospho-STAT3/total-STAT3 ratio (pSTAT3/tSTAT3, 79 and 86 kDa). Values are presented as mean ± S.E.M., * p < 0.05 vs. control group, # p < 0.05 vs. RT only group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Ctrl: control group, RT: radiotherapy only group (50 Gy), RT Los: RT plus losartan group. Images were captured with the Odyssey CLx machine and exported with Image Studio 5.2.5 software. The phospho-protein and total protein levels are represented in Figures S10 and S11. Black lines next to the Western blot images represent the position of protein markers with corresponding molecular weights. The uncropped Ponceau-stained membranes and the full-length Western blot images with the protein ladders are presented in Figures S12–S17.

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Source: PubMed

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