Abstract 193: 18-HEPE, An EPA Metabolite Released By Macrophages, Prevents Against Pressure Overload-induced Cardiac Remodeling

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N-3 polyunsaturated fatty acids (PUFAs) have potential cardiovascular benefit, although the mechanisms underlying this effect remain poorly understood. The present study investigated the impact of the enrichment of n-3 PUFAs in the setting of pressure overload induced cardiac hypertrophy using fat-1 mouse, a genetic model with elevated n-3 PUFA levels in tissues, as well as the possible cellular mechanism involved in such a role.

The fat-1 mice subjected to pressure overload by transverse aortic constriction showed less infiltration of macrophages and decreased interstitial fibrosis, leading to the preserved cardiac function as compared to wild type (WT) mice. Bone marrow (BM) transplantation experiments revealed that fat-1 transgenic BM cells, but not fat-1 transgenic cardiac cells, contributed the anti-remodeling effect, which was comparable between fat-1 and WT mice transplanted with fat-1 transgenic BM, but was absent in fat-1 mice transplanted with WT BM. In the co-culture assay with cardiac fibroblasts, the fat-1 transgenic macrophages showed anti-inflammatory and anti-fibrotic activities. Lipidomic analysis revealed selective enrichment of eicosapentaenoic acid (EPA) in fat-1 transgenic bone marrow (BM) cells and an EPA-metabolite 18-hydroxyeicosapentaenoic acid (18-HEPE) in fat-1 transgenic macrophages. 18-HEPE-rich milieu in the fat-1 transgenic heart was generated by BM-derived cells, most likely macrophages. 18-HEPE inhibited macrophage-mediated proinflammatory activation of cardiac fibroblasts in culture, and in vivo administration of 18-HEPE significantly attenuated the inflammation and fibrosis of hypertrophied hearts, resulting in improvement of cardiac function.

We found that the elevated n-3 PUFA level in BM-derived macrophages is responsible for cardiac protection, and 18-HEPE exhibited cardioprotective potential when administered in vivo.

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