Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cultured 3T6 fibroblast |
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Authors: | Diana Nieves Juan J Moreno |
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Institution: | (1) Department of Physiology, Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII s/n, Barcelona, 08028, Spain |
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Abstract: | Previous studies have demonstrated that arachidonic acid (AA) metabolites released by the cyclooxygenase pathway is involved
in serum-induced 3T6 fibroblast cycle progression and proliferation. However, these results also suggest that other AA cascade
pathways might be involved. Recently, we also described the role of hydroxyeicosatetraenoic acids, which are produced by cytochrome
P450 monooxygenases (CYP), in 3T6 fibroblast growth. AA can be also metabolized by the epoxygenase activity of CYP-producing
epoxyeicosatrienoic acids (EETs). Finally, the cytosolic epoxide hydrolases catalyze the hydration of the EETs, transforming
them into dihydroxyeicosatetraenoic acids (DHETEs). In this work, we have studied the role of the EETs/DHETEs on 3T6 fibroblasts
growth. Our results show that PDGF stimulates 3T6 fibroblast proliferation and 3H]thymidine incorporation, while the addition of 5,6-EET, 8,9-EET, 11,12-EET or 14,15-EET (0.1–1 μM) inhibit these processes.
Furthermore, 5,6-DHETE and 11,12-DHETE (0.1–1 μM) also inhibit cell proliferation and DNA synthesis. Interestingly, this growth
inhibition was correlated with an induction of apoptosis. Thus, we observed that in the presence of PDGF, EETs or DHETEs (0.1–1 μM)
induce phosphatidylserine externalization (as measured by annexin V-binding) and DNA fragmentation (as quantified using a
TUNEL assay). Our results show that calpain, as well as caspase-12 and caspase-3, are involved in these events. Therefore,
EETs and DHETEs have anti-proliferative and pro-apoptotic effects on PDGF-stimulated 3T6 fibroblasts. |
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Keywords: | Arachidonic acid EET Cell proliferation Cell death Cytochrome P-450 Eicosanoids |
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