The impact of X-rays on cardiac hydrometabolism and the regulatory role of AS-IV

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 3), p.113533, Article 113533
• Main Authors: Shangzu, Zhang, Qiyang, Li, Sichao, Dai, Yutong, Wang, Yangyang, Li, Yan, Chen, Gengqiang, Yang, Ting, Zhou, Zhiming, Miao, Fuxian, Liu, Liying, Zhang, Yongqi, Liu
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - radiation effects; AQPs; AS-IV; Cardiomyocyte edema; Cell Line; Connexin 43 - metabolism; Heart - drug effects; Heart - radiation effects; HIF-1α; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - radiation effects; Radiation Injuries, Experimental - metabolism; Radiation-induced heart disease; X-Rays
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113533

•X-rays induced abnormalities in the hydrometabolism of the heart and cardiomyocytes.•Myocardial edema is involved in the development of radiation-induced heart disease.•AS-IV can ameliorate X-ray induced cardiac damage by regulating hydrometabolism. 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.