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Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture
Nadia R Sutton1, Takanori Hayasaki1, Matthew C Hyman2
1Division of Cardiovascular Medicine, Department of Internal Medicine, and.
Abstract:
Mechanical complications of myocardial infarction (MI) are often fatal. Little is known about endogenous factors that predispose to myocardial rupture after MI. Ectonucleoside triphosphate diphosphohydrolase (CD39) could be a critical mediator of propensity to myocardial rupture after MI due to its role in modulating inflammation and thrombosis. Using a model of permanent coronary artery ligation, rupture was virtually abrogated in cd39 mice versus cd39 controls, with elevated fibrin and collagen deposition and marked neutrophil and macrophage influx. Macrophages were found to display increased surface expression of CD301 and CD206, marking a reparative phenotype, driven by increased extracellular ATP and IL-4 in the infarcted myocardium of cd39 mice. A myeloid-specific CD39-knockout mouse also demonstrated protection from rupture, with an attenuated rupture phenotype, suggesting that complete ablation of CD39 provides the greatest degree of protection in this model. Absence of CD39, either globally or in a myeloid lineage-restricted fashion, skews the phenotype toward alternatively activated (reparative) macrophage infiltration following MI. These studies reveal a previously unrecognized and unexpected role of endogenous CD39 to skew macrophage phenotype and promote a propensity to myocardial rupture after MI.
Insights
Ectonucleoside triphosphate diphosphohydrolase (CD39) absence protects against myocardial rupture after heart attack. This study reveals CD39 promotes rupture by skewing macrophage repair responses.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Mechanical complications, such as myocardial rupture, significantly increase mortality after myocardial infarction (MI).
- Endogenous factors predisposing to post-MI rupture remain poorly understood.
- Ectonucleoside triphosphate diphosphohydrolase (CD39) plays a role in inflammation and thrombosis, suggesting its involvement in post-MI complications.
Purpose of the Study:
- To investigate the role of CD39 in the propensity to myocardial rupture following MI.
- To elucidate the mechanisms by which CD39 influences cardiac healing and rupture.
Main Methods:
- Utilized a mouse model of permanent coronary artery ligation to induce MI.
- Compared myocardial rupture incidence and severity in wild-type and CD39-deficient (cd39-/-) mice.
- Analyzed inflammatory cell infiltration (neutrophils, macrophages) and extracellular matrix deposition (fibrin, collagen) in the infarcted myocardium.
- Assessed macrophage phenotype using surface markers (CD301, CD206) and quantified related signaling molecules (extracellular ATP, IL-4).
- Investigated the effect of myeloid-specific CD39 knockout on rupture phenotype.
Main Results:
- Myocardial rupture was virtually abrogated in cd39-/- mice compared to controls.
- Absence of CD39 led to increased fibrin and collagen deposition and significant neutrophil and macrophage infiltration.
- Macrophages in cd39-/- mice exhibited markers of a reparative phenotype (CD301, CD206), driven by elevated extracellular ATP and IL-4.
- Myeloid-specific CD39 knockout also conferred protection against rupture, indicating the importance of CD39 in myeloid cells.
- Global or myeloid-restricted CD39 deficiency shifted the post-MI phenotype towards alternatively activated (reparative) macrophage infiltration.
Conclusions:
- Endogenous CD39 promotes a propensity to myocardial rupture after MI.
- CD39 deficiency skews macrophage phenotype towards a reparative state, enhancing cardiac healing and reducing rupture risk.
- Targeting CD39 may offer a novel therapeutic strategy to prevent fatal mechanical complications following myocardial infarction.
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