PMID- 25032959
OWN - NLM
STAT- MEDLINE
DCOM- 20151218
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 7
DP  - 2014
TI  - Effects of exogenous recombinant APC in mouse models of ischemia reperfusion 
      injury and of atherosclerosis.
PG  - e101446
LID - 10.1371/journal.pone.0101446 [doi]
LID - e101446
AB  - Activated protein C (APC) is a serine protease that has both anticoagulant and 
      cytoprotective properties. The cytoprotective effects are protease activated 
      receptor 1 (PAR-1) and endothelial protein C receptor (EPCR) dependent and likely 
      underlie protective effects of APC in animal models of sepsis, myocardial 
      infarction and ischemic stroke. S360A-(A)PC, a variant (A)PC that has no 
      catalytic activity, binds EPCR and shifts pro-inflammatory signaling of the 
      thrombin-PAR-1 complex to anti-inflammatory signaling. In this study we 
      investigated effects of human (h)wt-PC, hS360A-PC, hwt-APC and hS360A-APC in 
      acute (mouse model of acute myocardial ischemia/reperfusion (I/R) injury) and 
      chronic inflammation (apoE-/- mouse model of atherosclerosis). All h(A)PC 
      variants significantly reduced myocardial infarct area (p<0.05) following I/R 
      injury. IL-6 levels in heart homogenates did not differ significantly between 
      sham, placebo and treatment groups in I/R injury. None of the h(A)PC variants 
      decreased number and size of atherosclerotic plaques in apoE-/- mice. Only 
      hS360A-APC slightly affected phenotype of plaques. IL-6 levels in plasma were 
      significantly (p<0.001) decreased in hwt-APC and hS360A-PC treated mice. In the 
      last group levels of monocyte chemotactic protein 1 (MCP-1) were significantly 
      increased (p<0.05). In this study we show that both hwt and hS360A-(A)PC protect 
      against acute myocardial I/R injury, which implies that protection from I/R 
      injury is independent of the proteolytic activity of APC. However, in the chronic 
      atherosclerosis model hwt and hS360-(A)PC had only minor effects. When the dose, 
      species and mode of (A)PC administration will be adjusted, we believe that (A)PC 
      will have potential to influence development of chronic inflammation as occurring 
      during atherosclerosis as well.
FAU - Wildhagen, Karin C A A
AU  - Wildhagen KC
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands.
FAU - Schrijver, Roy
AU  - Schrijver R
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands.
FAU - Beckers, Linda
AU  - Beckers L
AD  - Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The 
      Netherlands.
FAU - ten Cate, Hugo
AU  - ten Cate H
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands; Department of Internal 
      Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular 
      Research Institute Maastricht, Maastricht University, Maastricht, The 
      Netherlands.
FAU - Reutelingsperger, Chris P M
AU  - Reutelingsperger CP
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands.
FAU - Lutgens, Esther
AU  - Lutgens E
AD  - Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The 
      Netherlands.
FAU - Nicolaes, Gerry A F
AU  - Nicolaes GA
AD  - Department of Biochemistry, Cardiovascular Research Institute Maastricht, 
      Maastricht University, Maastricht, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140717
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, CD)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Endothelial Protein C Receptor)
RN  - 0 (IL10 protein, mouse)
RN  - 0 (Interleukin-6)
RN  - 0 (PROCR protein, human)
RN  - 0 (Protein C)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Recombinant Proteins)
RN  - 130068-27-8 (Interleukin-10)
SB  - IM
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Apolipoproteins E/genetics
MH  - Atherosclerosis/*drug therapy
MH  - Cell Line
MH  - Chemokine CCL2/blood/metabolism
MH  - Cytoprotection/drug effects
MH  - Endothelial Protein C Receptor
MH  - HEK293 Cells
MH  - Heart/physiopathology
MH  - Humans
MH  - Interleukin-10/blood
MH  - Interleukin-6/blood/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocardial Infarction/*drug therapy
MH  - Protein C/genetics/*pharmacology
MH  - Receptor, PAR-1/metabolism
MH  - Receptors, Cell Surface/metabolism
MH  - Recombinant Proteins/genetics/*pharmacology
MH  - Reperfusion Injury/*drug therapy
PMC - PMC4102480
COIS- Competing Interests: The authors confirm that co-authors Hugo ten Cate and Esther 
      Lutgens are PLOS ONE Editorial Board members. This does not alter the authors' 
      adherence to PLOS ONE Editorial policies and criteria.
EDAT- 2014/07/18 06:00
MHDA- 2015/12/19 06:00
PMCR- 2014/07/17
CRDT- 2014/07/18 06:00
PHST- 2014/03/13 00:00 [received]
PHST- 2014/06/06 00:00 [accepted]
PHST- 2014/07/18 06:00 [entrez]
PHST- 2014/07/18 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
PHST- 2014/07/17 00:00 [pmc-release]
AID - PONE-D-14-11418 [pii]
AID - 10.1371/journal.pone.0101446 [doi]
PST - epublish
SO  - PLoS One. 2014 Jul 17;9(7):e101446. doi: 10.1371/journal.pone.0101446. 
      eCollection 2014.