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

Abstract

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.