Document Detail


Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis.
MedLine Citation:
PMID:  23032324     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Coagulation disorders and reperfusion of ischemic myocardium are major causes of morbidity and mortality. Lectin pathway initiation complexes are composed of multimolecular carbohydrate recognition subcomponents and 3 lectin pathway-specific serine proteases. We have recently shown that the lectin pathway-specific carbohydrate recognition subcomponent mannose-binding lectin plays an essential role in the pathophysiology of thrombosis and ischemia/reperfusion injury. Thus, we hypothesized that the endogenous mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1) that inhibits complement activation in vitro also could be an in vivo regulator by attenuating myocardial schema/reperfusion injury and thrombogenesis when used at pharmacological doses in wild-type mice.
METHODS AND RESULTS: In 2 mouse models, MAP-1 preserves cardiac function, decreases infarct size, decreases C3 deposition, inhibits MBL deposition, and prevents thrombogenesis. Furthermore, we demonstrate that MAP-1 displaces MBL/ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex.
CONCLUSIONS: Our results suggest that the natural, endogenous inhibitor MAP-1 effectively inhibits lectin pathway activation in vivo. MAP-1 at pharmacological doses represents a novel therapeutic approach for human diseases involving the lectin pathway and its associated MASPs.
Authors:
Vasile I Pavlov; Mikkel-Ole Skjoedt; Ying Siow Tan; Anne Rosbjerg; Peter Garred; Gregory L Stahl
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-02
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-30     Completed Date:  2013-01-16     Revised Date:  2013-11-04    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2227-35     Citation Subset:  AIM; IM    
Affiliation:
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticoagulants / pharmacology,  therapeutic use*
Carotid Artery Thrombosis / chemically induced,  drug therapy*
Complement C3 / analysis
Complement Pathway, Mannose-Binding Lectin / drug effects*,  physiology
Depression, Chemical
Disease Models, Animal
Drug Evaluation, Preclinical
Humans
Lectins / metabolism
Mannose-Binding Protein-Associated Serine Proteases / antagonists & inhibitors*,  deficiency,  genetics,  pharmacology,  physiology,  therapeutic use
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Cardiovascular
Models, Immunological
Molecular Weight
Multiprotein Complexes / drug effects
Myocardial Infarction / drug therapy*,  pathology
Myocardial Reperfusion Injury / pathology,  prevention & control*,  ultrasonography
Protein Binding
Recombinant Fusion Proteins / metabolism
Grant Support
ID/Acronym/Agency:
AI089781/AI/NIAID NIH HHS; HL056086/HL/NHLBI NIH HHS; HL099130/HL/NHLBI NIH HHS; R01 AI089781/AI/NIAID NIH HHS; R01 HL056086/HL/NHLBI NIH HHS; R56 AI089781/AI/NIAID NIH HHS; R56 HL056086/HL/NHLBI NIH HHS; RC1 HL099130/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Complement C3; 0/Lectins; 0/Multiprotein Complexes; 0/Recombinant Fusion Proteins; 0/ficolin; EC 3.4.21.-/MASP-1 protein, mouse; EC 3.4.21.-/MASP1 protein, human; EC 3.4.21.-/Mannose-Binding Protein-Associated Serine Proteases
Comments/Corrections

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