title: Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction.
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 (Cpa3(Cre/+)) 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 Ca(2+) 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-Ca(2+) 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.
authors.affiliation: Institut 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.
authors.forename: Anta
authors.identifier: 0000-0002-0016-887X
authors.initials: A
authors.lastname: Ngkelo
authors.affiliation: Institut 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.
authors.forename: Adèle
authors.initials: A
authors.lastname: Richart
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 212015.
authors.forename: Jonathan A
authors.identifier: 0000-0002-5192-2860
authors.initials: JA
authors.lastname: Kirk
authors.affiliation: INSERM, U965, Hôpital Lariboisière-Fernand-Widal, Assistance Publique Hôpitaux de Paris, F-75010 Paris, France.
authors.forename: Philippe
authors.identifier: 0000-0003-3184-3740
authors.initials: P
authors.lastname: Bonnin
authors.affiliation: Institut 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.
authors.forename: Jose
authors.initials: J
authors.lastname: Vilar
authors.affiliation: Institut 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.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Lemitre
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, F-31004 Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Marck
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, F-31004 Toulouse, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Branchereau
authors.affiliation: Institut 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.
authors.forename: Sylvain
authors.identifier: 0000-0002-5268-0584
authors.initials: S
authors.lastname: Le Gall
authors.affiliation: Institut 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.
authors.forename: Nisa
authors.identifier: 0000-0002-1559-0774
authors.initials: N
authors.lastname: Renault
authors.affiliation: National Cytometry Platform, Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg.
authors.forename: Coralie
authors.initials: C
authors.lastname: Guerin
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 212015.
authors.forename: Mark J
authors.identifier: 0000-0002-4970-8988
authors.initials: MJ
authors.lastname: Ranek
authors.affiliation: Institut 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.
authors.forename: Anaïs
authors.identifier: 0000-0002-8081-8296
authors.initials: A
authors.lastname: Kervadec
authors.affiliation: Laboratoire d'Excellence INFLAMEX, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France INSERM, U1149, F-75018 Paris, France Centre National de la Recherche Scientifique (CNRS) ERL 8252, F-75018 Paris, France.
authors.forename: Luca
authors.identifier: 0000-0003-1222-0732
authors.initials: L
authors.lastname: Danelli
authors.affiliation: Laboratoire d'Excellence INFLAMEX, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France INSERM, U1149, F-75018 Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Gautier
authors.affiliation: Laboratoire d'Excellence INFLAMEX, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France INSERM, U1149, F-75018 Paris, France Centre National de la Recherche Scientifique (CNRS) ERL 8252, F-75018 Paris, France.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Blank
authors.affiliation: Laboratoire d'Excellence INFLAMEX, Université Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France INSERM, U1149, F-75018 Paris, France.
authors.forename: Pierre
authors.identifier: 0000-0002-3560-1389
authors.initials: P
authors.lastname: Launay
authors.affiliation: Institut 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.
authors.forename: Eric
authors.identifier: 0000-0002-6271-7125
authors.initials: E
authors.lastname: Camerer
authors.affiliation: Institut 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 Hôpital European George Pompidou, Assistance Publique Hôpitaux de Paris, F-75015 Paris, France.
authors.forename: Patrick
authors.identifier: 0000-0002-2350-2914
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Institut 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 Hôpital European George Pompidou, Assistance Publique Hôpitaux de Paris, F-75015 Paris, France.
authors.forename: Philippe
authors.identifier: 0000-0002-9845-4064
authors.initials: P
authors.lastname: Menasche
authors.affiliation: INSERM, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, F-31004 Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.affiliation: STROMALab, Etablissement Français du Sang, INSERM U1031, CNRS ERL 5311, Université de Toulouse, F-31004 Toulouse, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Luche
authors.affiliation: STROMALab, Etablissement Français du Sang, INSERM U1031, CNRS ERL 5311, Université de Toulouse, F-31004 Toulouse, France.
authors.forename: Louis
authors.identifier: 0000-0001-9647-3248
authors.initials: L
authors.lastname: Casteilla
authors.affiliation: STROMALab, Etablissement Français du Sang, INSERM U1031, CNRS ERL 5311, Université de Toulouse, F-31004 Toulouse, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Cousin
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 212015.
authors.forename: David A
authors.identifier: 0000-0003-1596-2299
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Institut 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 jean-sebastien.silvestre@inserm.fr.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D044464:Receptor, PAR-2; D019009:Proto-Oncogene Proteins c-kit; D017868:Cyclic AMP-Dependent Protein Kinases; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse; D002118:Calcium