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12(S)-HETE regulates the expression of IL-6 and IL-10 in cardiomyocytes through two distinct receptors, TXA2R and BLT2

Year: 2026

Type: article

Abstract: Cardiac inflammation contributes to the development and progression of heart failure (HF). Although cytokines are key mediators of cardiac inflammation, lipid-derived metabolites also play essential roles; however, their underlying mechanisms remain largely unexplored. Among these metabolites, 12 S-hydroxy-5 Z ,8 Z ,10 E , 14 Z -eicosatetraenoic acid (12(S)-HETE), an arachidonic acid-derived metabolite produced primarily by 15-lipoxygenase (ALOX15), has not been fully characterized in the heart. In neonatal rat cardiomyocytes, 12(S)-HETE significantly upregulated the expression of interleukin-6 (IL-6) and interleukin-10 (IL-10). The 12(S)-HETE-induced upregulation of IL-6 was suppressed by a thromboxane A2 receptor (TXA2R) antagonist, whereas treatment with a TXA2R agonist alone increased IL-6 expression, suggesting the involvement of TXA2R signaling. Conversely, pharmacological activation of leukotriene B4 receptor 2 (BLT2) attenuated the 12(S)-HETE-induced upregulation of IL-6. Treatment with a BLT2 agonist alone did not affect IL-6 expression but significantly increased IL-10 expression. In addition, both 12(S)-HETE and the BLT2 agonist activated extracellular signal-regulated kinase (ERK); this activation was inhibited by a BLT2 antagonist but not by a TXA2R antagonist. In a mouse model of myocardial infarction (MI), serum levels of 12-HETE (the combined amount of 12(S)-HETE and 12(R)-HETE) and cardiac expression of ALOX15 were increased. Collectively, these findings identify 12(S)-HETE as an inducible lipid mediator following MI that modulates pro- and anti-inflammatory cytokine expression in cardiomyocytes through coordinated activation of TXA2R and BLT2 signaling pathways. Targeting 12(S)-HETE signaling may therefore represent a potential therapeutic strategy for preventing inflammation-associated cardiac remodeling and HF.

Source: Biochemistry and Biophysics Reports

DOI: 10.1016/j.bbrep.2026.102716