5,6‐dihydroxy‐8Z,11Z,14Z,17Z‐eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4‐mediated signaling
Koji Kobayashi, Kohei Ashina, Sandra Derouiche, Taiki Hamabata, Tatsuro Nakamura, Nanae Nagata, Shinya Takenouchi, Makoto Tominaga, Takahisa Murata
Abstract
Abstract 5,6‐dihydroxy‐8Z,11Z,14Z,17Z‐eicosatetraenoic acid (5,6‐DiHETE) is an eicosapentaenoic acid‐derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6‐DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4 days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6‐DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6‐DiHETE (0.1‐1 μM, 30 minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50 nM). Intracellular Ca 2+ imaging also showed that pretreatment with 5,6‐DiHETE (1 μM, 10 minutes) reduced GSK1016790A‐induced intracellular Ca 2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6‐DiHETE (50 µg kg −1 day −1 ) during the healing phase accelerated the recovery from DSS‐induced colitis. Pathological studies showed that the administration of 5,6‐DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6‐DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.