期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 287, 期 5, 页码 C1192-C1201出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00158.2004
关键词
capacitative Ca2+ entry; proliferation; vascular smooth muscle
资金
- NHLBI NIH HHS [R01 HL066012, HL-69758, HL-54043, HL-66012, HL-64945, HL-66941] Funding Source: Medline
Extracellular ATP and intracellular cyclic AMP response element-binding protein ( CREB, a transcription factor) promote cell proliferation in many cell types. The canonical transient receptor potential ( TRPC) channels, which putatively participate in forming store- and receptor-operated Ca2+ channels, have been implicated in the pulmonary vascular remodeling processes. A link between extracellular ATP, CREB activation, and TRPC4 channel expression and activity has not been shown in human pulmonary artery smooth muscle cells (PASMC). Long-term (24 - 48 h) treatment of human PASMC with a low dose ( 100 muM) of ATP, which did not trigger a transient rise in free cytosolic Ca2+ concentration ([Ca2+](i)) when applied acutely to the cells, caused marked increases in CREB phosphorylation and TRPC4 protein expression. The time course indicated that the ATP-mediated CREB phosphorylation preceded TRPC4 upregulation, whereas transfection of a nonphosphorylatable CREB mutant abolished ATP-mediated TRPC4 expression. Furthermore, treatment of human PASMC with ATP also enhanced the amplitude of capacitative Ca2+ entry (CCE) induced by passive store depletion, whereas the small interfering RNA specifically targeting TRPC4 attenuated ATP-mediated increases in TRPC4 expression and CCE amplitude and inhibited ATP-induced PASMC proliferation. These data suggest that low-dose ATP exerts part of its mitogenic effect in human PASMC via CREB-mediated upregulation of TRPC4 channel expression and activity and the subsequent increase in CCE and [Ca2+](i).
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