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

VL - 126

SP - 2227

EP - 2235

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 18

ER -