Upregulation of the maresin pathway and PGE metabolism in the failing human left ventricle.

Chronic inflammation is involved in the pathogenesis of heart failure (HF), with cardiac remodeling and fibrosis resulting from sustained myofibroblasts activation. This is due to an imbalance between pro-inflammatory and pro-resolving mediators including specialized pro-resolving lipid mediators (SPM). This study aimed to explore the SPM pathway and its crosstalks with other pathways in human left ventricle (LV) samples from HF-patients and non-HF donors or in ex-vivo cultured cardiac fibroblasts. The SPM content was measured in LV samples from HF-patients and donors. Resolvin D5 (RvD5) and maresin-1 (MaR1) were the most abundant SPM and with similar levels between both groups, at baseline. Following exposure to exogenous DHA or EPA, SPM levels increased in both groups but MaR1 and 7(S)-MaR1 have shown a significantly higher increase in ex-vivo LV samples from HF-patients compared to donors. Furthermore, we found a higher expression of the related enzymes (lipoxygenases, LOXs): 15-LOX-1, 15-LOX-2 and 12-LOX in HF-patients LV in vitro samples. Finally, the MaR1 receptor (LGR6) expression was also increased in these LV samples from HF-patients compared to donors. In addition, we investigated the role of SPM on COX-2/mPGES-1/prostaglandin E (PGE) pathway previously described as cardioprotective in HF. In cardiac fibroblasts from HF-patients, exposed to inflammatory conditions, RvD1 and MaR1 increased PGE biosynthesis while RvD5 decreased it. Taken together, our data show an enhanced MaR1 biosynthesis and functional pathway in the heart from HF-patients. Furthermore, in cultured cardiac fibroblasts, MaR1 increased the PGE concentration levels. These data highlighted novel aspects of inflammation regulation in HF physiopathology.