Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

Anta Ngkelo, Adèle Richart, Jonathan A. Kirk, Philippe Bonnin, Jose Vilar, Mathilde Lemitre, Pauline Marck, Maxime Branchereau, Sylvain Le Gall, Nisa Renault, Coralie Guerin, Mark J. Ranek, Anaïs Kervadec, Luca Danelli, Gregory Gautier, Ulrich Blank, Pierre Launay, Eric Camerer, Patrick Bruneval, Philippe MenascheChristophe Heymes, Elodie Luche, Louis Casteilla, Béatrice Cousin, Hans Reimer Rodewald, David A. Kass, Jean Sébastien Silvestre

Research output: Contribution to journalArticlepeer-review

Abstract

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit-independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force-Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.

Original languageEnglish (US)
Pages (from-to)1353-1374
Number of pages22
JournalJournal of Experimental Medicine
Volume213
Issue number7
DOIs
StatePublished - Jun 27 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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