Bradykinin limits infarction when administered as an adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS.
J MOL CELL CARDIOL
185 - 193.
Attenuation of reperfusion injury by growth factors has recently been linked to recruitment of phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), a pathway also linked to the phosphorylation of eNOS by bradykinin. We, therefore, hypothesised that bradykinin would limit infarct size when given as an adjunct to reperfusion.Using an isolated perfused mouse heart model of ischaemia/reperfusion injury, we show that 100 nmol/I bradykinin, administered upon reperfusion, attenuates infarct size (32 +/- 2% to 22 +/- 2%, P < 0.01). This protection was abrogated by concomitant administration of the PI3K inhibitor, wortmannin (100 nmol/1), whereas wortmannin alone had no impact upon infarct size (31 +/- 3% and 30 +/- 1 %, respectively). In eNOS knockout hearts, bradykinin was not seen to be protective (31 2% versus 32 2%), yet knockout hearts could be rescued with the nitric oxide donor, S-nitroso-N-acetyl penicillamine (SNAP) (1 mumol/l) (17 +/- 4%, P < 0.01). Using western blot analysis, we show that bradykinin administration results in rapid, robust phosphorylation of both Akt and eNOS, greater than that seen in control hearts upon reperfusion (Akt/eNOS phosphorylation: 68 +/- 7/122 +/- 29 AU versus 32 +/- 5/47 +/- 10 AU respectively, P < 0.01). This pattern of Akt phosphorylation was mimicked in the absence of eNOS, whereas Akt phosphorylation was inhibited by wortmannin. Exogenous nitric oxide administration had no impact upon Akt phosphorylation.Therefore, we demonstrate that exogenous bradykinin, administered at reperfusion, limits infarct size with concomitant rapid phosphorylation of Akt and eNOS, and that this protection is dependent upon the presence of eNOS. These results may open new avenues for research into clinical limitation of reperfusion injury following acute myocardial infarction. (C) 2003 Elsevier Science Ltd. All rights reserved.
|Title:||Bradykinin limits infarction when administered as an adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS|
|Keywords:||reperfusion injury, PI3 kinase, Akt, eNOS, nitric oxide, infarct size, bradykinin, NITRIC-OXIDE SYNTHASE, GROWTH-FACTOR-I, CONVERTING-ENZYME-INHIBITOR, ACUTE MYOCARDIAL-INFARCTION, ENDOTHELIAL-CELLS, VENTRICULAR-FUNCTION, KINASE PATHWAYS, LATE-PHASE, RAT-HEART, INJURY|
|UCL classification:||UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
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