Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis
Vasile I Pavlov1, Mikkel-Ole Skjoedt, Ying Siow Tan
1Center 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.
Insights
Mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1) protects the heart from injury and clotting. Pharmacological doses of MAP-1 may offer a new treatment for diseases linked to the lectin pathway.
Area of Science:
- Immunology
- Cardiovascular Science
- Complement System
Background:
- Coagulation disorders and myocardial ischemia/reperfusion injury are significant causes of mortality.
- The lectin pathway, initiated by mannose-binding lectin (MBL) complexes, is implicated in thrombosis and ischemia/reperfusion.
- Endogenous MBL/ficolin-associated protein-1 (MAP-1) inhibits complement activation in vitro.
Purpose of the Study:
- To investigate the in vivo efficacy of MAP-1 in attenuating myocardial ischemia/reperfusion injury and thrombogenesis.
- To determine if pharmacological doses of MAP-1 can serve as a therapeutic agent.
Main Methods:
- Utilized two mouse models to assess the effects of MAP-1.
- Measured cardiac function, infarct size, C3 deposition, and MBL deposition.
- Investigated MAP-1's mechanism by examining its displacement of MBL/ficolin-associated serine proteases (MASPs) from the MBL complex.
Main Results:
- MAP-1 administration preserved cardiac function and reduced infarct size in mouse models.
- MAP-1 decreased C3 and MBL deposition and prevented thrombogenesis.
- MAP-1 was shown to displace MASP-1, MASP-2, and MASP-3 from the MBL complex.
Conclusions:
- Endogenous MAP-1 effectively inhibits lectin pathway activation in vivo.
- Pharmacological doses of MAP-1 represent a potential novel therapeutic strategy for lectin pathway-associated diseases.
- MAP-1's ability to inhibit MBL complexes and associated MASPs offers a targeted therapeutic approach.
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.
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