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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1087.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Activated Protein C Protects Against Myocardial Ischemia/ Reperfusion Injury via Inhibition of Apoptosis and Inflammation

Sarah T.B.G. Loubele; C. Arnold Spek; Peter Leenders; René van Oerle; Hella L. Aberson; Karly Hamulyák; Gary Ferrell; Charles T. Esmon; Henri M.H. Spronk; Hugo ten Cate

From the Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis (S.T.G.L., P.L., R.v.O., H.M.H.S., H.t.C.), the Department of Pharmacology (P.L.), and the Department of Internal Medicine, Division of Haematology (K.H.), Cardiovascular Research Institute Maastricht, Maastricht University Medical Center+, The Netherlands; the Center for Experimental and Molecular Medicine (C.A.S., H.L.A.), Academic Medical Center, Amsterdam, The Netherlands; and the Cardiovascular Biology Research Program (G.F., C.T.E.), Oklahoma Medical Research Foundation, and Howard Hughes Medical Institute, Oklahoma City.

Correspondence to Sarah T.B.G. Loubele, Maastricht University Medical Center+, Departments of Internal Medicine and Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, PO Box 616, Uns 50: Box 8, 6200 MD Maastricht, The Netherlands. E-mail sarah.loubele{at}bioch.unimaas.nl

Objective— In spite of major advances in reperfusion therapy for patients presenting with acute coronary syndrome, long-term morbidity is still substantial. A limitation of initial treatment of myocardial ischemia is the lack of prevention of ischemia/reperfusion (I/R) injury. Activated protein C (APC), a crucial mediator in the coagulation process, plays a prominent role in the crosstalk between coagulation and inflammation and provides cytoprotective effects via inhibition of apoptosis and inflammation in several human and animal studies.

Methods and Results— APC was administered in an animal model for myocardial I/R. APC largely inhibited early myocardial I/R injury after varying reperfusion times, an effect that was absent on administration of heparin, a nonspecific anticoagulant agent. The protective effects of APC were absent in case of absence or blockade of protease activated receptor-1 (PAR-1), indicating a critical role for PAR-1 in this process. Furthermore, we showed a strong antiapoptotic effect of APC in the early phase of reperfusion combined with an antiinflammatory effect at an early stage (IL-6), as well as at a later stage (leukocyte infiltration).

Conclusions— APC exerts strong protective effects on early myocardial I/R injury, primarily via inhibition of apoptosis and inflammation, which are regulated via PAR-1.

Activated protein C (APC) is studied for its cytoprotective properties in several human and animal studies. APC largely inhibited early myocardial I/R injury after varying reperfusion times. Furthermore, a strong antiapoptotic and antiinflammatory effect of APC was observed and revealed a critical role for PAR-1 in this process.

Key Words: activated protein C • myocardial ischemia/reperfusion • inflammation • apoptosis • protease activated receptor-1