Hypoxia activates nuclear factor of activated T cells
isoforms c3 (
NFATc3), a Ca(2+)-dependent
transcription factor in murine pulmonary arteries (PAs), and
NFATc3 has been proved to be implicated in
hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation, but it remains unclear whether
NFATc3 acts on the apoptosis of PASMCs, an important step in PAs remodeling. Our laboratory has demonstrated that 15-hydroxyeicosatetraenoic
acid (15-HETE) is a key factor in
hypoxia-induced PA remodeling and can increase PASMC intracellular Ca(2+) ([Ca(2+)](i)) in rats. It is possible that
NFATc3 is related with the function of
15-HETE anti-apoptosis during
hypoxia. Our results identified that
NFATc3 was mainly localized in rat PASMCs and was upregulated in PAs during
hypoxia-induced rat
pulmonary hypertension (PH), while this effect was inhibited by administration of
nordihydroguaiaretic acid (NDGA), a
15-lipoxygenase (15-LO) inhibitor. Moreover,
hypoxia and exogenous
15-HETE promoted the expression and nuclear translocation of
NFATc3 in PASMCs, which was inhibited by NDGA or
small interfering RNA targeted to rat 15-LO1 or 15-LO2. Furthermore, endogenous
15-HETE induced by
hypoxia and exogenous
15-HETE suppressed serum deprivation-induced loss of rat PASMCs survival and prevented
annexin V binding, mitochondrial membrane potential depolarization, DNA nick end labeling and
chromatin condensation. Although all these effects were suppressed after the cells were treated with
cyclosporin A (a
calcineurin/NFAT inhibitor), it aggravated the apoptosis induced by serum deprivation. Thus, all these results indicate that 15-HETE-mediated PASMCs anti-apoptosis in hypoxic PH via the Ca(2+)-
NFATc3 pathway.