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Hypoxia increases AP-1 binding activity by enhancing capacitative Ca²⁺ entry in human pulmonary artery endothelial cells

Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of California, San Diego, California 92103-8382

Submitted 26 December 2002 ; accepted in final form 3 August 2003

Activating protein (AP)-1 transcription factors modulate expression of genes involved in cell proliferation and migration. Chronic hypoxia increases pulmonary artery smooth muscle cell proliferation by upregulating AP-1-responsive genes encoding for endothelium-derived vasoactive and mitogenic factors implicated in pulmonary hypertension development. The expression of AP-1 transcription factors is sensitive to changes in cytosolic free [Ca²⁺] ([Ca²⁺]_cyt). Capacitative Ca²⁺ entry (CCE) via store-operated Ca²⁺ channels (SOC) is an important mechanism for raising [Ca²⁺]_cyt in pulmonary artery endothelial cells (PAEC). Using combined molecular biological, fluorescence microscopy, and biophysical approaches, we examined the effect of chronic hypoxia (3% O₂, 72 h) on AP-1 DNA binding activity, CCE, and transient receptor potential (TRP) gene expression in human (h) PAEC. EMSA showed that AP-1 binding to hPAEC nuclear protein extracts was significantly enhanced by hypoxia, the increase being dependent on store-operated Ca²⁺ influx and sensitive to La³⁺, an SOC inhibitor. Hypoxia also increased basal [Ca²⁺]_cyt, the amount of CCE produced by store depletion with cyclopiazonic acid, and the amplitude of SOC-mediated currents (I_SOC). The increases of CCE amplitude and I_SOC current density by hypoxia were paralleled by enhanced TRPC4 mRNA and protein expression. Hypoxia-enhanced CCE and TRPC4 expression were also attenuated by La³⁺. These data suggest that hypoxia increases AP-1 binding activity by enhancing Ca²⁺ influx via La³⁺-sensitive TRP-encoded SOC channels in hPAEC. The Ca²⁺-mediated increase in AP-1 binding may play an important role in upregulating AP-1-responsive gene expression, in stimulating pulmonary vascular cell proliferation and, ultimately, in pulmonary vascular remodeling in patients with hypoxia-mediated pulmonary hypertension.

activating protein-1; store-operated channels; transient receptor potential genes

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