Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.
Mónika Gabriella KovácsZsuzsanna Z A KovácsZoltán VargaGergő SzűcsMarah FreiwanKatalin FarkasBence KőváriGábor CserniAndrás KristonFerenc KovácsPéter HorváthImre FöldesiTamás CsontZsuzsanna KahánMárta SárközyPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- radiation induced
- angiotensin ii
- transforming growth factor
- signaling pathway
- epithelial mesenchymal transition
- angiotensin converting enzyme
- heart failure
- left ventricular
- radiation therapy
- growth factor
- cell proliferation
- pi k akt
- vascular smooth muscle cells
- induced apoptosis
- pulmonary hypertension
- mitral valve
- cardiac resynchronization therapy
- hypertrophic cardiomyopathy
- south africa
- atrial fibrillation
- risk assessment
- randomized controlled trial
- locally advanced
- spinal cord
- spinal cord injury
- transcription factor
- coronary artery disease
- human health
- anti inflammatory
- small molecule
- bone marrow
- rectal cancer
- liver fibrosis