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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 10, 2005; DOI: 10.1124/jpet.105.093849

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Received for publication August 8, 2005.
Revised October 6, 2005.
Accepted for publication November 9, 2005.

Angiotensin I -Converting Enzyme Inhibitors Block PKC{epsilon} by Activating Bradykinin B1 Receptors in Human Endothelial Cells

Sinisa Stanisavljevic 1, Tatjana Ignjatovic 1, Peter A. Deddish 1, Viktor Brovkovych 2, Kai Zhang 2, Ervin G. Erdos 1*, Randal A. Skidgel 1

1 UIC College of Medicine 2 UIC College of Medicine

* Address correspondence to: E-mail: egerdos{at}uic.edu

Abstract

Angiotensin I-converting enzyme (ACE) inhibitors are widely used to treat patients with cardiovascular and kidney diseases, but inhibition of ACE alone does not fully explain the beneficial effects. We reported that ACE inhibitors directly activate bradykinin B1 receptor at the canonical Zn2+ binding site, leading to prolonged NO production in endothelial cells. PKC{epsilon}, a novel PKC isoform is upregulated in myocardium after infarction, suggesting a role in the development of cardiac dysfunction. In cytokine-treated human lung microvascular endothelial cells, B1 receptor activation by ACE inhibitors (enalaprilat, quinaprilat) or peptide ligands (des-Arg10-Lys1-bradykinin, des-Arg9-bradykinin) inhibited PKC{epsilon} with an IC50 = 7 x 10-9 M. Despite the reported differences in binding affinity to receptor, the two peptide ligands were equally active, even when inhibitor blocked the cleavage of Lys1, thus the conversion by aminopeptidase. The synthetic undecapeptide (LLPHEAWHFAR) representing the binding site for ACE inhibitors on human B1 receptors reduced PKC{epsilon} inhibition by enalaprilat, but not by peptide agonist. A combination of inducible and endothelial NO synthase inhibitors (1400W and L-NNA, 2 µM) significantly reduced inhibition by enalaprilat (100 nM), whereas the NO donor DETA-NONOate (100 µM) inhibited PKC{epsilon} activity just as the B1 ligands did. In conclusion, NO generated by B1 receptor activation inhibited PKC{epsilon}.


Key words: B1 agonists, cytokines, endothelial cells, kinins, peptide receptor, protein kinase


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