Shangzu Zhang, Qiyang Li, Sichao Dai, Yutong Wang, Yangyang Li, Yan Chen, Gengqiang Yang, Ting Zhou, Zhiming Miao, Fuxian Liu, Liying Zhang, Yongqi Liu
Gansu University of Chinese Medicine, LanZhou, China.
Gansu University of Chinese Medicine, LanZhou, China; Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China; Gansu Institute of Cardiovascular Diseases, LanZhou, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113533. doi: 10.1016/j.intimp.2024.113533. Epub 2024 Oct 31.
Radiation-induced cardiac injury has emerged as a significant pathological entity, with many studies focusing on the fibrotic changes in myocardial tissue. However, these do not offer solutions for the clinical prevention and treatment of radiation-induced heart disease. Regulating hydrometabolism presents a potential therapeutic target for the management of cardiovascular diseases. This research seeks to explore the impacts of irradiation on cardiac hydrometabolism and its regulatory mechanisms.
The impact of X-ray radiation on cardiac and cardiomyocyte hydrometabolism was studied through in vivo and in vitro experiments, examining the pharmacological effects and mechanisms of PX-478 and AS-IV interventions in cardiomyocytes.
28 days after direct chest irradiation with 20 Gy X-rays, C57BL/6 mice exhibited an increased heart wet-to-dry weight ratio, significant enlargement of cardiomyocyte cross-sectional area, and elevated protein expression of HIF-1α, AQP1, AQP4, Cx43, Caspase3, and Bax, with decreased expression of Bcl-2. Irradiation with 6 Gy X-rays induced edema and damage in AC16 and HL-1 cardiomyocytes at 24, 48, and 72 h, with increased expression of HIF-1α, AQP1, AQP4, and Cx43 proteins post-radiation. Inhibition of HIF-1α ameliorated edema and apoptosis in AC16 and HL-1 cardiomyocytes, reducing the expression of HIF-1α, AQP1, AQP4, and Cx43 proteins. AS-IV demonstrated strong binding affinity with HIF-1α, and successfully attenuated the expression levels of HIF-1α, AQP1, AQP4, and Cx43 proteins, alleviating edema, mitochondrial swelling, and apoptosis in AC16 and HL-1 cardiomyocytes. Furthermore, AS-IV improved cardiomyocyte edema by restoring the activity of Na/K-ATPase.
Aberrant activation of the HIF-1α/AQPs/Cx43 axis is a key mechanism in X-ray-induced cardiomyocyte edema and damage. AS-IV can ameliorate X-ray induced cardiac damage by regulating hydrometabolism.
辐射诱导的心脏损伤已成为一种重要的病理实体，许多研究聚焦于心肌组织的纤维化改变。然而，这些研究并未为辐射诱导的心脏病的临床预防和治疗提供解决方案。调节水代谢是心血管疾病管理的一个潜在治疗靶点。本研究旨在探讨辐射对心脏水代谢的影响及其调控机制。
通过体内和体外实验研究X射线辐射对心脏和心肌细胞水代谢的影响，检测PX - 478和黄芪甲苷（AS - IV）干预心肌细胞的药理作用及机制。
用20 Gy X射线直接胸部照射28天后，C57BL/6小鼠心脏湿重与干重比增加，心肌细胞横截面积显著增大，缺氧诱导因子 - 1α（HIF - 1α）、水通道蛋白1（AQP1）、水通道蛋白4（AQP4）、连接蛋白43（Cx43）、半胱天冬酶3（Caspase3）和Bax蛋白表达升高，Bcl - 2表达降低。用6 Gy X射线照射24、48和72小时后，AC16和HL - 1心肌细胞出现水肿和损伤，辐射后HIF - 1α、AQP1、AQP4和Cx43蛋白表达增加。抑制HIF - 1α可改善AC16和HL - 1心肌细胞的水肿和凋亡，降低HIF - 1α、AQP1、AQP4和Cx43蛋白的表达。AS - IV与HIF - 1α表现出很强的结合亲和力，并成功降低了HIF - 1α、AQP1、AQP4和Cx43蛋白的表达水平，减轻了AC16和HL - 1心肌细胞的水肿、线粒体肿胀和凋亡。此外，AS - IV通过恢复钠钾ATP酶的活性改善心肌细胞水肿。
HIF - 1α/AQPs/Cx43轴的异常激活是X射线诱导心肌细胞水肿和损伤的关键机制。AS - IV可通过调节水代谢改善X射线诱导的心脏损伤。
