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Hepoxilin A(3) protects beta-cells from apoptosis in contrast to its precursor, 12-hydroperoxyeicosatetraenoic acid

Item Type:Article
Title:Hepoxilin A(3) protects beta-cells from apoptosis in contrast to its precursor, 12-hydroperoxyeicosatetraenoic acid
Creators Name:Zafiriou, M.P. and Zelarayan, L.C. and Noack, C. and Renger, A. and Nigam, S. and Siafaka-Kapadai, A.
Abstract:Pancreatic beta-cells have a deficit of scavenging enzymes such as catalase (Cat) and glutathione peroxidase (GPx) and therefore are susceptible to oxidative stress and apoptosis. Our previous work showed that, in the absence of cytosolic GPx in insulinoma RINm5F cells, an intrinsic activity of 12 lipoxygenase (12(S)-LOX) converts 12S-hydroperoxyeicosatetraenoic acid (12(S)-HpETE) to the bioactive epoxide hepoxilin A(3) (HXA(3)). The aim of the present study was to investigate the effect of HXA(3) on apoptosis as compared to its precursor 12(S)-HpETE and shed light upon the underlying pathways. In contrast to 12(S)-HpETE, which induced apoptosis via the extrinsic pathway, we found HXA(3) not only to prevent it but also to promote cell proliferation. In particular, HXA(3) suppressed the pro-apoptotic BAX and upregulated the anti-apoptotic Bcl-2. Moreover, HXA(3) induced the anti-apoptotic 12(S)-LOX by recruiting heat shock protein 90 (HSP90), another anti-apoptotic protein. Finally, a co-chaperone protein of HSP90, protein phosphatase 5 (PP5), was upregulated by HXA(3), which counteracted oxidative stress-induced apoptosis by dephosphorylating and thus inactivating apoptosis signal-regulating kinase 1 (ASK1). Taken together, these findings suggest that HXA(3) protects insulinoma cells from oxidative stress and, via multiple signaling pathways, prevents them from undergoing apoptosis.
Keywords:HXA(3), 12(S)-HpETE, Apoptosis, Pancreatic beta Cell, Oxidative Stress, Animals, Rats
Source:Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Page Range:361-369
Date:June 2011
Official Publication:https://doi.org/10.1016/j.bbalip.2011.03.002
PubMed:View item in PubMed

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