Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.
Angiotensin II Type 1 Receptor Blockers
/ therapeutic use
Animals
Chymases
/ metabolism
Disease Models, Animal
Heart Failure
/ prevention & control
Hypertrophy, Left Ventricular
/ drug therapy
Losartan
/ therapeutic use
Male
Mitogen-Activated Protein Kinase 1
/ metabolism
Mitogen-Activated Protein Kinase 3
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Radiation Fibrosis Syndrome
/ drug therapy
Rats
Rats, Sprague-Dawley
Smad2 Protein
/ analysis
Smad3 Protein
/ analysis
Transforming Growth Factor beta1
/ analysis
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
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
30 Nov 2021
30 Nov 2021
Historique:
received:
31
10
2021
revised:
25
11
2021
accepted:
26
11
2021
entrez:
10
12
2021
pubmed:
11
12
2021
medline:
21
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34884782
pii: ijms222312963
doi: 10.3390/ijms222312963
pmc: PMC8657420
pii:
doi:
Substances chimiques
Angiotensin II Type 1 Receptor Blockers
0
Smad2 Protein
0
Smad2 protein, rat
0
Smad3 Protein
0
Smad3 protein, rat
0
Tgfb1 protein, rat
0
Transforming Growth Factor beta1
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Mapk1 protein, rat
EC 2.7.11.24
Mitogen-Activated Protein Kinase 1
EC 2.7.11.24
Mitogen-Activated Protein Kinase 3
EC 2.7.11.24
Chymases
EC 3.4.21.39
Losartan
JMS50MPO89
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Research, Development and Innovation Office
ID : GINOP-2.3.2-15-2016-00040
Organisme : National Research, Development and Innovation Office
ID : NKFIH FK129094
Organisme : National Research, Development and Innovation Office
ID : EFOP-3.6.2-16-2017-00006
Organisme : Ministry of Human Capacities
ID : 20391-3/2018/FEKUSTRAT
Organisme : Ministry of Human Capacities
ID : ÚNKP-21-3-SZTE-97 to M.G.K., ÚNKP-21-3-SZTE-98 to Z.Z.A.K., and ÚNKP-20-5-SZTE-166 to M.S
Organisme : Hungarian Academy of Sciences
ID : János Bolyai Research Fellowship
Organisme : National Research, Development and Innovation Office
ID : EFOP-3.6.3-VEKOP-16-2017-00009
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