Astragaloside IV alleviates radiation-induced heart disease by regulating energy metabolism

Background: Radiation-induced heart disease (RIHD) has emerged as a critical complication compromising the long-term survival of Cancer patients undergoing radiotherapy. Although targeting myocardial energy metabolism is a promising therapeutic strategy for cardiovascular diseases, the molecular mechanisms underlying ionizing radiation-induced cardiomyocyte metabolic dysregulation and subsequent cardiac injury remain unclear.

Purpose: This study aims to explore the mechanism by which Astragaloside IV (AS-Ⅳ) alleviates RIHD through the regulation of energy metabolism.

Methods: This study established mouse and cellular models of radiation-induced heart injury to investigate the effects of X-ray radiation on energy metabolism in the hearts of C57BL/6 mice and in cardiomyocyte cell lines (AC16 and H9C2). By integrating untargeted metabolomics with experimental validation, we elucidated the pharmacological effects and molecular mechanisms of the HIF-1α Inhibitor (PX-478) and AS-IV intervention in mouse heart tissue and cardiomyocytes.

Results: In vitro experiments demonstrated that X-rays at doses of 6 Gy and above induced damage and abnormal energy metabolism in H9C2 and AC16 cardiomyocytes at 24, 48, and 72 h, respectively. These abnormalities were primarily characterized by inhibited cell proliferation, increased Apoptosis, decreased ATP content, and elevated lactate and lipid accumulation. These phenomena may be associated with the abnormal activation of the HIF-1α/PPARγ signaling pathway. Additionally, AS-IV effectively mitigated radiation-induced cardiomyocyte injury by regulating HIF-1α/PPARγ-mediated glycolysis and triglyceride synthesis metabolism, as well as by alleviating mitochondrial damage.

Conclusion: Abnormal activation of the HIF-1α/PPARγ axis may represent a potential mechanism underlying X-ray-induced abnormalities in myocardial energy metabolism and cellular damage. Furthermore, AS-IV has the potential to alleviate radiocardiac injury by modulating energy metabolism and restoring mitochondrial function.

AQPs; AS-IV; HIF-1α; Metabolomics; Radiation-induced heart disease; Radiotherapy.