Conclusions
Our findings demonstrate that radiation facilitates cardiac fibroblast activation by enhancing p38/ET-1 signaling in cardiomyocytes, revealing the IR/p38/ET-1 regulatory axis in RIMF for the first time. DHA effectively inhibits fibroblast activation by targeting p38/ET-1 and can be recognized as a promising protective agent against RIMF.
Purpose
Radiation-induced myocardial fibrosis (RIMF) is a severe delayed complication of thoracic irradiation (IR). Endothelin-1 (ET-1) is critical in cardiac fibroblast activation, and docosahexaenoic acid (DHA) is protective against various cardiac diseases. This study aimed to explore the roles of ET-1 in RIMF and the potential of DHA in preventing RIMF.
Results
Radiation increased ET-1 expression and secretion by increasing p38 phosphorylation in cardiomyocytes, and ET-1 markedly promoted the activation of cardiac fibroblasts, which were characterized by enhanced fibroblast proliferation, migration, and α-SMA expression. Cardiomyocyte-derived ET-1 mediated radiation-induced fibroblast activation by targeting the PI3K-AKT and MEK-ERK pathways in fibroblasts. DHA suppressed ET-1 levels by blocking p38 signaling in cardiomyocytes and significantly attenuated the activation of cardiac fibroblasts induced by the IR/ET-1 axis. Importantly, DHA decreased collagen deposition and α-SMA expression, alleviating cardiac fibrosis caused by radiation in mouse models. Conclusions: Our findings demonstrate that radiation facilitates cardiac fibroblast activation by enhancing p38/ET-1 signaling in cardiomyocytes, revealing the IR/p38/ET-1 regulatory axis in RIMF for the first time. DHA effectively inhibits fibroblast activation by targeting p38/ET-1 and can be recognized as a promising protective agent against RIMF.