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      Kininase I-type carboxypeptidases enhance nitric oxide production in endothelial cells by generating bradykinin B1 receptor agonists.

      American Journal of Physiology - Heart and Circulatory Physiology
      Bradykinin, analogs & derivatives, pharmacology, Capillaries, metabolism, Carboxypeptidases, Cell Line, Cell Membrane, enzymology, Endothelium, Vascular, cytology, drug effects, Humans, Immunohistochemistry, Interferon-gamma, Interleukin-1, Kallidin, Lysine Carboxypeptidase, Nitric Oxide, biosynthesis, Pulmonary Circulation, Receptor, Bradykinin B1, Receptors, Bradykinin, agonists, Stimulation, Chemical, Subcellular Fractions, Up-Regulation

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          Abstract

          Kininase I-type carboxypeptidases convert native kinin agonists for B(2) receptors into B(1) receptor agonists by specifically removing the COOH-terminal Arg residue. The membrane localization of carboxypeptidase M (CPM) and carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity. Nitric oxide (NO) release from human lung microvascular endothelial cells (HLMVEC) was measured directly in real time with a porphyrinic microsensor. Bradykinin (1-100 nM) elicited a transient (5 min) peak of generation of NO that was blocked by the B(2) antagonist HOE 140, whereas B(1) agonist des-Arg(10)-kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC with 5 ng/ml interleukin-1beta and 200 U/ml interferon-gamma for 16 h upregulated B(1) receptors as shown by an approximately fourfold increase in prolonged (>20 min) output of NO in response to des-Arg(10)-kallidin, which was blocked by the B(1) antagonist des-Arg(10)-Leu(9)-kallidin. B(2) receptor agonists bradykinin or kallidin also generated prolonged NO production in treated HLMVEC, which was significantly reduced by either a B(1) antagonist or carboxypeptidase inhibitor, and completely abolished with a combination of B(1) and B(2) receptor antagonists. Furthermore, CPM and CPD activities were increased about twofold in membrane fractions of HLMVEC treated with interleukin-1beta and interferon-gamma compared with control cells. Immunostaining localized CPD primarily in a perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show that cellular kininase I-type carboxypeptidases can enhance kinin signaling and NO production by converting B(2) agonists to B(1) agonists, especially in inflammatory conditions.

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