Journal
MICROVASCULAR RESEARCH
Volume 78, Issue 1, Pages 33-39Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mvr.2009.04.005
Keywords
Apoptosis; Calpain; Calpastatin; NADPH oxidase; Endothelial cells; Sepsis
Categories
Funding
- Heart & Stroke Foundation of Ontario [6315, 6461]
- New Investigator Award from Heart & Stroke Foundation of Canada
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This study was to investigate the role of calpain in the apoptosis of pulmonary microvascular endothelial cells (PMEC) during septic plasma stimulation. Septic plasma was collected from endotoxemic mice. In cultured PMEC, incubation with septic plasma stimulated calpain activation, increased caspase-3 activity and induced apoptotic cell death. These effects of septic plasma were abrogated by knockdown of calpain-1 but not calpain-2 using specific siRNA. Consistently, treatment with calpain inhibitor-III, or over-expression of calpastatin, an endogenous calpain inhibitor significantly decreased apoptosis induced by septic plasma. Septic plasma also induced NADPH oxidase activation and reactive oxygen species (ROS) production. Inhibiting NADPH oxidase or scavenging ROS attenuated calpain activity and decreased apoptosis in PMEC during septic plasma stimulation. In summary, our study demonstrates that ROS produced from NADPH oxidase stimulates calpain-1 activation, which induces apoptosis under septic conditions. Thus, targeting calpain-1/calpastatin may represent a potential strategy to protect against endothelial injury in sepsis. (C) 2009 Elsevier Inc. All rights reserved.
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