Angiotensin I-converting enzyme inhibitors block protein kinase C epsilon by activating bradykinin B1 receptors in human endothelial cells |
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Authors: | Stanisavljevic Sinisa Ignjatovic Tatjana Deddish Peter A Brovkovych Viktor Zhang Kai Erdös Ervin G Skidgel Randal A |
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Affiliation: | Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue (MC 868), Chicago, IL 60612, USA. |
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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 nitric oxide (NO) production in endothelial cells. Protein kinase C (PKC) epsilon, a novel PKC isoform, is up-regulated 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 Lys(1), thus the conversion by aminopeptidase. The synthetic undecapeptide (LLPHEAWHFAR) representing the binding site for ACE inhibitors on human B(1) receptors reduced PKC epsilon inhibition by enalaprilat but not by peptide agonist. A combination of inducible and endothelial NO synthase inhibitors, 1400W [N-(3(aminomethyl) benzyl) acetamidine dihydrochloride] and N omega-nitro-L-arginine (2 microM), significantly reduced inhibition by enalaprilat (100 nM), whereas the NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (100 microM) inhibited PKC epsilon activity just as the B1 ligands did. In conclusion, NO generated by B1 receptor activation inhibits PKC epsilon. |
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