Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy

Abstract

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR.

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

“…Cardiac morphology and function were assessed by transthoracic echocardiography as described previously [ 59 , 60 ], at weeks 1, 3, and 15 to monitor the development of RIHD. Rats were anesthetized with 2% isoflurane (Forane, Aesica, Queenborough Limited, Queenborough, UK).…”

“…Blood was collected from the abdominal aorta at weeks 1, 3, and 15. Total blood count and hematocrit were measured from whole blood by a hematology analyzer (XE-2100, Sysmex Corporation, Kobe, Japan) [ 60 ] to characterize the severity of systemic inflammation and the compensatory increase in red blood cell synthesis associated with lung and heart damage due to RT.…”

“…On the digital HE images, cardiomyocyte cross-sectional areas were measured to verify the development of LVH at the cellular level. For the evaluation, the Biology Image Analysis Software (BIAS) was used [ 60 ]. BIAS (internal built, dated December 2019; , accessed on 29 November 2021) is developed by Single-Cell Technologies Ltd., Szeged, Hungary, and the first publicly available version is expected to be released in late 2021.…”

“…Quantitative RT-PCR was performed with gene-specific primers to monitor mRNA expression as described previously [ 59 , 60 ]. RNA was isolated using Qiagen RNeasy Fibrous Tissue Mini Kit (Qiagen, Hilden, Germany) from heart tissue.…”

“…To investigate gene expression changes at the protein level, a standard Western blot technique was used as described previously [ 59 , 60 ]. AT1R (41 kDa), AT2R (41 kDa), SMAD2/3 (52 and 60 kDa), TGF-βRII (85 kDa), STAT3 (79 and 86 kDa), pSTAT3 (79 and 86 kDa), AKT (60 kDa), pAKT (60 kDa), ERK1/2 (42 and 44 kDa), and pERK1/2 (42 and 44 kDa) with GAPDH (37 kDa) loading background were assessed at weeks 1, 3, and 15.…”