Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis

Vasile I Pavlov; Mikkel-Ole Skjoedt; Ying Siow Tan; Anne Rosbjerg; Peter Garred; Gregory L Stahl

doi:10.1161/circulationaha.112.123968

Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis

Vasile I Pavlov, Mikkel-Ole Skjoedt, Ying Siow Tan, Anne Rosbjerg, Peter Garred, Gregory L Stahl

56 Citations (Scopus)

Abstract

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.

Original language	English
Book series	Circulation. Supplement
Volume	126
Issue number	18
Pages (from-to)	2227-35
Number of pages	9
ISSN	0009-7322
DOIs	https://doi.org/10.1161/circulationaha.112.123968
Publication status	Published - 30 Oct 2012

Keywords

Animals
Anticoagulants
Carotid Artery Thrombosis
Complement C3
Complement Pathway, Mannose-Binding Lectin
Depression, Chemical
Disease Models, Animal
Drug Evaluation, Preclinical
Humans
Lectins
Mannose-Binding Protein-Associated Serine Proteases
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Cardiovascular
Models, Immunological
Molecular Weight
Multiprotein Complexes
Myocardial Infarction
Myocardial Reperfusion Injury
Protein Binding
Recombinant Fusion Proteins
Ultrasonography
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/circulationaha.112.123968

CIRCULATIONAHA.112.123968Final published version, 1.57 MB

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title = "Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis",

abstract = "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.",

keywords = "Animals, Anticoagulants, Carotid Artery Thrombosis, Complement C3, Complement Pathway, Mannose-Binding Lectin, Depression, Chemical, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Lectins, Mannose-Binding Protein-Associated Serine Proteases, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Cardiovascular, Models, Immunological, Molecular Weight, Multiprotein Complexes, Myocardial Infarction, Myocardial Reperfusion Injury, Protein Binding, Recombinant Fusion Proteins, Ultrasonography, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Pavlov, {Vasile I} and Mikkel-Ole Skjoedt and {Siow Tan}, Ying and Anne Rosbjerg and Peter Garred and Stahl, {Gregory L}",

year = "2012",

month = oct,

day = "30",

doi = "10.1161/circulationaha.112.123968",

language = "English",

volume = "126",

pages = "2227--35",

journal = "Circulation. Supplement",

issn = "0009-7322",

publisher = "Lippincott Williams & Wilkins",

number = "18",

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TY - JOUR

T1 - Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis

AU - Pavlov, Vasile I

AU - Skjoedt, Mikkel-Ole

AU - Siow Tan, Ying

AU - Rosbjerg, Anne

AU - Garred, Peter

AU - Stahl, Gregory L

PY - 2012/10/30

Y1 - 2012/10/30

N2 - 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.

AB - 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.

KW - Animals

KW - Anticoagulants

KW - Carotid Artery Thrombosis

KW - Complement C3

KW - Complement Pathway, Mannose-Binding Lectin

KW - Depression, Chemical

KW - Disease Models, Animal

KW - Drug Evaluation, Preclinical

KW - Humans

KW - Lectins

KW - Mannose-Binding Protein-Associated Serine Proteases

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Models, Cardiovascular

KW - Models, Immunological

KW - Molecular Weight

KW - Multiprotein Complexes

KW - Myocardial Infarction

KW - Myocardial Reperfusion Injury

KW - Protein Binding

KW - Recombinant Fusion Proteins

KW - Ultrasonography

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1161/circulationaha.112.123968

DO - 10.1161/circulationaha.112.123968

M3 - Journal article

C2 - 23032324

SN - 0009-7322

VL - 126

SP - 2227

EP - 2235

JO - Circulation. Supplement

JF - Circulation. Supplement

IS - 18

ER -

Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis

Abstract

Keywords

UN SDGs

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