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(Hypertension. 2000;35:292.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Interleukin-1ß Regulates the Human Brain Natriuretic Peptide Promoter via Ca²⁺-Dependent Protein Kinase Pathways

Quan He; Margot C. LaPointe

From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.

Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. E-mail mclapointe{at}aol.com

Abstract—We have shown that interleukin-1ß (IL-1ß) 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-1ß. We questioned whether Ca²⁺ and Ca²⁺-dependent pathways mediate IL-1ß 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-1ß–stimulated promoter activity. Long-term treatment with thapsigargin, which depletes intracellular Ca²⁺ stores, decreased basal promoter activity and blocked the effect of IL-1ß. Inhibition of protein kinase C completely blocked IL-1ß–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-1ß 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-1ß; and (4) the phosphatase calcineurin is not involved in IL-1ß regulation of the hBNP promoter. Thus, Ca²⁺ and Ca²⁺-dependent pathways are critical to IL-1ß regulation of the hBNP promoter.

Key Words: protein kinases • calcium • calcineurin • myocytes

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