Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

Area of Science:

• Cardiovascular biology
• Immunology
• Molecular medicine

Background:

• The innate immune response after myocardial infarction (MI) is crucial for tissue repair but can cause further damage through excessive inflammation.
• Exaggerated cytokine and chemokine release promotes leukocyte infiltration, exacerbating injury post-MI.

Purpose of the Study:

• To investigate the role of the a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in regulating neutrophil recruitment after MI.
• To evaluate the therapeutic potential of targeting this axis to mitigate MI-induced tissue damage.

Main Methods:

• Analysis of myocardial biopsies from patients with ischemia-driven cardiomyopathy to assess ADAM10 levels.
• Pharmacological inhibition and genetic deletion of ADAM10 in mouse models of MI.
• Assessment of survival, cardiac function, scar size, and inflammatory markers, including neutrophil infiltration and IL-1β levels.

Main Results:

• Myocardial ADAM10 was upregulated in patients with ischemia-driven cardiomyopathy.
• ADAM10 inhibition or deletion in mice post-MI improved survival, cardiac function, and reduced scar size.
• Targeting ADAM10 reduced IL-1β-dependent inflammation, neutrophil egress from bone marrow, and myocardial infiltration by blocking CX3CL1 shedding.

Conclusions:

• The ADAM10/CX3CL1 axis is a key regulator of neutrophil recruitment and inflammation early after MI.
• Targeting ADAM10 offers a promising therapeutic strategy to improve outcomes following myocardial infarction.
• This study provides novel insights into cardiomyocyte-derived signaling in acute cardiac injury.