Stimulation of NFAT‐dependent transcription activity by agonists and hypoxia in pulmonary arterial smooth muscle cells

Abstract

Nuclear factors of activated T‐cells (NFATs) are Ca2+‐sensitive transcription factors regulated by calcineurin, and play critical roles in inflammation and cell proliferation. Several previous studies showed that calcineurin/NFAT pathway is involved in the pathogenesis of pulmonary hypertension. We have found recently that NFATc3 is predominantly expressed in rat pulmonary arterial smooth muscle cells (PASMCs), and hNFATc3‐EGFP fusion protein translocates to the nucleus upon stimulation in rat PASMCs. In this study, NFAT‐dependent transcription activity was further examined in primary cultured rat PASMCs using a 4xNFAT‐luciferasereporter. NFAT‐dependent luciferase acitivity was enhanced significantly by ionomycin+PMA, PDGF, ET‐1, and hypoxia (2% O2 for 24 hr). The stimulatory effects of PDGF and hypoxia could be blocked by SKF‐96365 and nifedipine, respectively. Moreover, the effects of ionomycin+PMA and PDGF were further potentiated in PASMCs exposed to hypoxia. Since many agonists and growth factors are involved in hypoxic pulmonary hypertension, these observations suggest that hypoxia may interact synergistically with agonists to enhance NFAT‐dependent gene transcription in PASMCs. (Supported by HL0771835, HL075134)