期刊
HYPERTENSION
卷 35, 期 1, 页码 292-296出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.35.1.292
关键词
protein kinases; calcium; calcineurin; myocytes
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL028982] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL-03188, HL-28982] Funding Source: Medline
We have shown that interleukin-1 beta (IL-1 beta) activates the human brain natriuretic peptide (hBNP) promoter via a transcriptional mechanism. Others have reported that changes in intracellular calcium (Ca2+) mediate the action of IL-1 beta. We questioned whether Ca2+ and Ca2+-dependent pathways mediate IL-1 beta regulation of the hBNP promoter in cardiac myocytes. The hBNP promoter (-1818 to + 100) coupled to a luciferase cDNA reporter gene was transferred into neonatal cardiac myocytes. Cells were then treated with agents that modify Ca2+ levels or inhibit Ca2+-dependent kinases, and luciferase activity was measured as an index of hBNP promoter activity. The Ca2+ ionophore A23187 increased hBNP promoter activity; however, neither EGTA nor nifedipine reduced IL-1 beta-stimulated promoter activity. Long-term treatment with thapsigargin, which depletes intracellular Ca2+ stores, decreased basal promoter activity and blocked the effect of IL-1 beta. Inhibition of protein kinase C completely blocked IL-1 beta-stimulated hBNP promoter activity, whereas inhibition of Ca2+/calmodulin-dependent kinase II decreased promoter activity by 40%. In contrast, inhibition of the Ca2+-regulated phosphatase calcineurin by cyclosporin A had no effect. These data suggest that (1) Ca2+ activates the hBNP promoter; (2) release of Ca2+ from intracellular stores is important to IL-1 beta regulation of the hBNP promoter, but transport via voltage-sensitive Ca2+ channels is not; (3) protein kinase C and Ca2+/calmodulin-dependent kinase II mediate the action of IL-1 beta; and (4) the phosphatase calcineurin is not involved in IL-1 beta regulation of the hBNP promoter. Thus, Ca2+ and Ca2+-dependent pathways are critical to IL-1 beta regulation of the hBNP promoter.
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