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J Thorac Cardiovasc Surg 2006;131:21-27
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1

Jonathan R.S. Day, MRCS a , Kenneth M. Taylor, MD, FRCS, FRCSE, FESC, FSA a , Elaine A. Lidington, PhD a , Justin C. Mason, PhD, FRCP a , Dorian O. Haskard, DM, PhD a , Anna M. Randi, MD, PhD a , R. Clive Landis, PhD b , *

a Eric Bywaters Centre, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London, United Kingdom
b Edmund Cohen Laboratory for Vascular Research, CDRC, University of the West Indies, Bridgetown, Barbados.

* Address for reprints: R. Clive Landis, PhD, Edmund Cohen Laboratory for Vascular Research, CDRC, University of the West Indies, Barbados. (Email: clandis{at}uwichill.edu.bb).

OBJECTIVE: Thrombin is generated in significant quantities during cardiopulmonary bypass and mediates adverse events, such as platelet aggregation and proinflammatory responses, through activation of the high-affinity thrombin receptor protease-activated receptor 1, which is expressed on platelets and endothelium. Thus antagonism of protease-activated receptor 1 might have broad therapeutic significance. Aprotinin, used clinically to reduce transfusion requirements and the inflammatory response to bypass, has been shown to inhibit protease-activated receptor 1 on platelets in vitro and in vivo. Here we have examined whether aprotinin inhibits endothelial protease-activated receptor 1 activation and resulting proinflammatory responses induced by thrombin.

METHODS: Protease-activated receptor 1 expression and function were examined in cultured human umbilical vein endothelial cells after treatment with {alpha}-thrombin at 0.02 to 0.15 U/mL in the presence or absence of aprotinin (200-1600 kallikrein inhibitory units/mL). Protease-activated receptor 1 activation was assessed by using an antibody, SPAN-12, which detects only the unactivated receptor, and thrombin-mediated calcium fluxes. Other thrombin-dependent inflammatory pathways investigated were phosphorylation of the p42/44 mitogen-activated protein kinase, upregulation of the early growth response 1 transcription factor, and production of the proinflammatory cytokine interleukin 6.

RESULTS: Pretreatment of cultured endothelial cells with aprotinin significantly spared protease-activated receptor 1 receptor cleavage (P < .0001) and abrogated calcium fluxes caused by thrombin. Aprotinin inhibited intracellular signaling through p42/44 mitogen-activated protein kinase (P < .05) and early growth response 1 transcription factor (P < .05), as well as interleukin 6 secretion caused by thrombin (P < .005).

CONCLUSIONS: This study demonstrates that endothelial cell activation by thrombin and downstream inflammatory responses can be inhibited by aprotinin in vitro through blockade of protease-activated receptor 1. Our results provide a new molecular basis to help explain the anti-inflammatory properties of aprotinin reported clinically.

Abbreviations and Acronyms CPB = cardiopulmonary bypass; Egr = early growth response; HRP = horseradish peroxidase; HUVEC = human umbilical vein endothelial cell; IL = interleukin; KIU = kallikrein inhibitory units; MAP = mitogen-activated protein; PAR = protease-activated receptor; SD = standard deviation; TRAP = thrombin receptor agonist peptide




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