2. Academic Validation
  3. Docosahexaenoic Acid Attenuates Radiation-Induced Myocardial Fibrosis by Inhibiting the p38/ET-1 Pathway in Cardiomyocytes

Docosahexaenoic Acid Attenuates Radiation-Induced Myocardial Fibrosis by Inhibiting the p38/ET-1 Pathway in Cardiomyocytes

  • Int J Radiat Oncol Biol Phys. 2022 Dec 16;S0360-3016(22)03519-2. doi: 10.1016/j.ijrobp.2022.11.007.
Yuchen Liu 1,  Pengxiang Chen 1,  Tianyu Liu 2,  Bo Cheng 2,  Changhua Sun 3,  Huixian Xin 2,  Zhihua Wen 4,  Yufeng Cheng 2
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China; Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.
  • 2 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China.
  • 3 Shandong Institute for Food and Drug Control, Jinan, China.
  • 4 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China. Electronic address: [email protected].
PMID: 36529557 DOI: 10.1016/j.ijrobp.2022.11.007
Abstract

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.

Methods and materials: Hematoxylin and eosin, sirius red, and Masson trichrome staining were carried out to evaluate the histopathologic conditions in mouse models. Enzyme-linked immunosorbent assays were used to detect the concentration of ET-1 in serum and cell supernatants. Western blotting, immunofluorescence, and immunohistochemistry were used to assess the protein levels. The phenotypic alterations of cardiac fibroblasts were evaluated by cell proliferation/migration assays and α-smooth muscle actin (α-SMA) detection.

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.

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