PMID- 15320513
OWN - NLM
STAT- MEDLINE
DCOM- 20041202
LR  - 20201208
IS  - 1570-1611 (Print)
IS  - 1570-1611 (Linking)
VI  - 2
IP  - 2
DP  - 2004 Apr
TI  - Prevention of endothelial cell injury by activated protein C: the molecular 
      mechanism(s) and therapeutic implications.
PG  - 125-33
AB  - Activated protein C (APC), a natural anticoagulant, is formed from protein C by 
      the action of thrombin bound to thrombomodulin on the endothelial cell surface. 
      APC regulates the coagulation system by inactivating the activated form of 
      factors V and VIII in the presence of protein S. Tumor necrosis factor-alpha 
      (TNF-alpha) plays critical roles in the development of disseminated intravascular 
      coagulation, acute respiratory distress syndrome and shock in sepsis by inducing 
      endothelial cell damage through activation of neutrophils. APC reduces the 
      pulmonary endothelial cell injury and hypotension in rats administered endotoxin 
      (ET) by inhibiting TNF-alpha production through inhibition of its transcription. 
      Furthermore, APC reduces the ischemia/reperfusion-induced renal injury and the 
      stress-induced gastric mucosal injury in rats. Inhibition by APC of the 
      endothelial cell damage inhibited the decrease in the endothelial production of 
      prostacyclin in vivo. These therapeutic effects could not be attributed to its 
      anticoagulant effects, but to inhibition of TNF-alpha production. APC inhibits 
      ET-induced TNF-alpha production in vitro in human monocytes by inhibiting 
      activation of NFkappaB and AP-1 by inhibiting degradation of IkappaB and 
      mitogen-activated protein kinase pathways, respectively. Recombinant APC was 
      reported to reduce the mortality of patients with severe sepsis. These 
      observations strongly suggest that APC might be involved not only in regulation 
      of the coagulation system, but in regulation of inflammatory responses by 
      preventing endothelial cell injury. Furthermore, APC reduced the spinal cord 
      injury induced by compression-trauma or ischemia/reperfusion by inhibiting 
      TNF-alpha production in rats, suggesting that APC may be a potential therapeutic 
      agent for spinal cord injury in which only limited therapeutic measures are 
      currently available.
FAU - Okajima, Kenji
AU  - Okajima K
AD  - Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto 
      University, School of Medicine, Honjo 1-1-1, Kumamoto 860-0811, Japan. 
      whynot@kaiju.medic.kumamoto-u.ac.jp
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United Arab Emirates
TA  - Curr Vasc Pharmacol
JT  - Current vascular pharmacology
JID - 101157208
RN  - 0 (Blood Coagulation Factors)
RN  - 0 (Protein C)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (activated protein C receptor)
RN  - EC 3.4.21.- (Serine Endopeptidases)
SB  - IM
MH  - Animals
MH  - Blood Coagulation/physiology
MH  - Blood Coagulation Factors/physiology
MH  - Clinical Trials as Topic
MH  - Endothelium, Vascular/cytology/drug effects/*metabolism
MH  - Humans
MH  - Hypotension/etiology/metabolism
MH  - Lung/blood supply
MH  - Monocytes/drug effects/metabolism
MH  - Protein C/*metabolism
MH  - Receptors, Cell Surface/physiology
MH  - Respiratory Distress Syndrome/etiology/metabolism/pathology
MH  - Sepsis/complications/drug therapy/metabolism
MH  - Serine Endopeptidases/*metabolism/therapeutic use
MH  - Spinal Cord Injuries/drug therapy/metabolism
MH  - Stomach Ulcer/etiology/metabolism
MH  - Stress, Psychological/complications
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors
RF  - 70
EDAT- 2004/08/24 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/08/24 05:00
PHST- 2004/08/24 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/08/24 05:00 [entrez]
AID - 10.2174/1570161043476429 [doi]
PST - ppublish
SO  - Curr Vasc Pharmacol. 2004 Apr;2(2):125-33. doi: 10.2174/1570161043476429.