Role of MAPKs and NF‐κB in the Development of Cellular Hypertrophy by 8‐ Hydroxyeicosatetraenoic acids in Human Ventricular Cardiomyocyte, RL‐14 Cell Line

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Recent studies have established the role of mid-chain hydroxyeicosatetraenoic acids (HETEs) in the development of cardiovascular disease. Among these mid-chains, 8-HETE has been reported to have proliferator and pro-inflammatory action. However, whether 8-HETE can induce cardiac hypertrophy has never been investigated before. Therefore, the overall objective of the present study is to elucidate the potential hypertrophic effect of 8-HETE in the human ventricular cardiomyocytes, RL-14 cells, and to explore the mechanism(s) involved. Our results showed that 8-HETE induced cellular hypertrophy in RL-14 cells as evidence by the induction of cardiac hypertrophy markers ANP, BNP, α-MHC, and β-MHC in a concentration- and time-dependent manner and the increase in cell surface area. Mechanistically, 8-HETE was able to induce the binding activity of NF-κB to its responsive element and significantly induced the phosphorylation of ERK1/2. The induction of cellular hypertrophy was associated with a proportional increase in the formation of dihydroxyeicosatrienoic acids (DHETs) parallel to the increase of soluble epoxide hydrolase enzyme activity. Blocking the induction of NF-κB, ERK1/2 and sEH signaling pathways significantly inhibited 8-HETE-induced cellular hypertrophy. Our study provides the first evidence that 8-HETEs induce cellular hypertrophy in RL-14 cells through MAPKs and NF-κB dependent mechanism.