NFATc3 pathway participates in the process that 15-LO/15-HETE protects pulmonary artery smooth muscle cells against apoptosis during hypoxia

• Published in: Journal of receptors and signal transduction Vol. 34; no. 4; p. 270
• Main Authors: Ran, Yajuan, Wu, Hong, Wei, Liuping, Yu, Xiufeng, Chen, Jianguo, Li, Shanshan, Zhang, Lei, Lou, Jianshi, Zhu, Daling
• Format: Journal Article
• Language: English
• Published: England 01.08.2014
• Subjects: Animals; Annexin A5 - metabolism; Apoptosis - drug effects; Arachidonate 15-Lipoxygenase - metabolism; Calcium - metabolism; Cell Hypoxia - drug effects; Cell Proliferation - drug effects; Hydroxyeicosatetraenoic Acids - metabolism; Masoprocol - administration & dosage; Membrane Potential, Mitochondrial - drug effects; Mice; Myocytes, Smooth Muscle - metabolism; NFATC Transcription Factors - metabolism; Pulmonary Artery - metabolism; Rats; Signal Transduction - drug effects; NFATc3; hypoxia; 15-HETE; apoptosis; pulmonary hypertension
• ISSN: 1532-4281
• DOI: 10.3109/10799893.2014.917322

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.