Interdisciplinary Center of Excellence and MEDICS Research Group, Department of Biochemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary.
Department of Oncotherapy, Albert Szent-Györgyi Medical School, University of Szeged, H-6720 Szeged, Hungary.
Int J Mol Sci. 2021 Nov 30;22(23):12963. doi: 10.3390/ijms222312963.
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.
放射性心脏病（RIHD）是胸部放射治疗后潜在的迟发性副作用，由于导致心力衰竭的复杂发病机制，导致左心室肥厚（LVH）和纤维化。血管紧张素 II 受体阻滞剂（ARB），包括氯沙坦，常用于控制各种病因引起的心力衰竭。ARB 在 RIHD 中的抗重构作用的临床前证据不足，而临床研究的结果存在争议。我们旨在研究氯沙坦在 RIHD 大鼠模型中的作用。雄性 Sprague-Dawley 大鼠分为三组进行研究：（1）对照组，（2）仅放射治疗（RT）组，（3）用氯沙坦（口服 10mg/kg/天）治疗的 RT 组，并随访 1、3 或 15 周。在放射治疗后 15 周，氯沙坦减轻了超声心动图和组织学上的 LVH 和纤维化迹象，并通过 qPCR 降低了心肌中糜酶、结缔组织生长因子和转化生长因子-β的过度表达；同样，通过 Western blot 测定的 SMAD2/3 蛋白水平也降低了。在 RT 两组中，在第 15 周时，存活相关的磷酸化 AKT/AKT 和磷酸化 ERK1,2/ERK1,2 比值增加。氯沙坦的抗重构作用似乎与我们的 RIHD 模型中糜酶和 TGF-β/SMAD 信号通路的几个元素的抑制有关。
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