Mast Cell Arachidonate 5-lipoxygenase Deficiency Attenuates Ischemia/Reperfusion-induced Cardiac Fibrotic Remodeling in Mice by Limiting Mast Cell Leukotrienes

We found that specific knockout of ALOX5 in mast cells in mice reduces mast cell aggregation, lowers local LT levels, alleviates myocardial fibrosis, and improves cardiac function. Mechanistically, TNF-α drives the colocalization of ALOX5 and FLAP at the mast cell nuclear membrane, promoting the synthesis and release of LTB4 and cysteinyl leukotrienes, which in turn activate leukotriene receptors on cardiac fibroblasts and promote fibroblast proliferation, migration, and myofibroblast differentiation via the NF-κB, AKT, and STAT3 pathways.

Genetic or pharmacological inhibition of ALOX5 in mast cells blocks LT production and suppresses fibroblast activation, suggesting that targeting ALOX5 in mast cells is a potential therapeutic strategy for reducing fibrotic remodeling following I/R.