Activated protein C protects against myocardial ischemia/ reperfusion injury via inhibition of apoptosis and inflammation.
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.


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.
Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands. sarah.loubele@bioch.unimaas.nl
Sarah T B G
ST
Loubele
C Arnold
CA
Spek
Peter
P
Leenders
René
R
van Oerle
Hella L
HL
Aberson
Karly
K
Hamulyák
Gary
G
Ferrell
Charles T
CT
Esmon
Henri M H
HM
Spronk
Hugo
H
ten Cate
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D011486:Protein C / Q000008:administration & dosage*; D044463:Receptor, PAR-1 / Q000187:drug effects / Q000502:physiology
D000925:Anticoagulants; D011486:Protein C; D044463:Receptor, PAR-1