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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
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Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction
Anta Ngkelo1, Adèle Richart1, Jonathan A Kirk2
1Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-970, Centre de Recherche Cardiovasculaire, Université Paris Descartes, Sorbonne Paris Cité, F-75015 Paris, France.
The Journal of Experimental Medicine
|June 30, 2016
Summary
Mast cells (MCs) are crucial for cardiac repair after myocardial infarction (MI). MC deficiency impairs heart function by altering cardiomyocyte contractility through protein kinase A (PKA) signaling.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Physiology
Background:
- Acute myocardial infarction (MI) triggers inflammatory responses that drive cardiac remodeling.
- Mast cells (MCs) are implicated in post-MI cardiac remodeling, but their precise role and mechanisms remain unclear.
- Previous studies using c-Kit mutant mice are confounded by pleiotropic effects on multiple cell types.
Purpose of the Study:
- To elucidate the specific role of mast cells (MCs) in cardiac function and remodeling following myocardial infarction (MI).
- To investigate the cellular origins and differentiation of MCs in the post-MI heart.
- To identify the molecular mechanisms by which MCs influence cardiomyocyte contractility.
Main Methods:
- Utilized c-Kit-independent, mast cell-deficient (Cpa3(Cre/+)) mice to specifically assess MC function after MI.
- Tracked MC progenitor origin, migration, and differentiation into mature MCs within the post-MI heart.
- Assessed cardiac function, cardiomyocyte contractility, myofilament calcium (Ca2+) sensitivity, and protein kinase A (PKA) signaling pathways.
Main Results:
- MC deficiency resulted in significantly reduced post-ischemic cardiac function and depressed cardiomyocyte contractility.
- MC deficiency led to myofilament Ca2+ desensitization, associated with increased PKA activity and hyperphosphorylation of troponin I and myosin-binding protein C.
- MC-specific tryptase was identified as a key mediator, regulating PKA activity in cardiomyocytes via protease-activated receptor 2 (PAR-2) signaling.
Conclusions:
- Cardiac mast cells play a critical, previously unrecognized role in modulating cardiomyocyte contractility after MI.
- MCs regulate cardiac function by influencing PKA-mediated phosphorylation of myofilament proteins, thereby altering force-Ca2+ interactions.
- This MC-cardiomyocyte crosstalk represents a novel therapeutic target for managing cardiac dysfunction post-MI.
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