Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+entry in human pulmonary artery endothelial cells
| Autor: | Shen Zhang, Ivana Fantozzi, Carmelle V. Remillard, Jason X.-J. Yuan, Oleksandr Platoshyn, Randy T. Cowling |
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| Rok vydání: | 2003 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.medical_specialty Indoles Endothelium Physiology Hypertension Pulmonary Cell Pulmonary Artery Biology Physiology (medical) Internal medicine medicine.artery medicine Humans Gene Silencing Enzyme Inhibitors RNA Small Interfering Hypoxia Transcription factor Cells Cultured TRPC Cation Channels Nuclear Proteins Cell Biology Hypoxia (medical) medicine.disease Pulmonary hypertension Cell biology Transcription Factor AP-1 Endothelial stem cell Endocrinology medicine.anatomical_structure Chronic Disease Pulmonary artery Calcium Calcium Channels Endothelium Vascular medicine.symptom Intracellular |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 285:L1233-L1245 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00445.2002 |
| Popis: | 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+]cytin 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 ( ISOC). The increases of CCE amplitude and ISOCcurrent 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. |
| Databáze: | OpenAIRE |
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