title: Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation.
abstract: The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4(+) T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4(+) T-cell and M2-macrophage recruitment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Feng
authors.initials: F
authors.lastname: Wan
authors.affiliation: Department of Physiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France; Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75020, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Unités Mixtes de Recherche Scientifique 1155, Paris, France; and.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.affiliation: Department of Medicine/Cardiology Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas;
authors.forename: Claude Jourdan
authors.initials: CJ
authors.lastname: Le Saux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Daigo
authors.initials: D
authors.lastname: Sawaki
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France; Département Hospitalo-Universitairé Ageing Thorax-Vessels Blood (DHU A-TVB), Department of Physiology, AP-HP, Henri Mondor Hospital, Créteil, France; DHU A-TVB, Department of Cardiology, AP-HP, Henri Mondor Hospital, Créteil, France;
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Rande
authors.affiliation: Department of Physiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Tenon Hospital, Paris, France; Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75020, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Unités Mixtes de Recherche Scientifique 1155, Paris, France; and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France; Département Hospitalo-Universitairé Ageing Thorax-Vessels Blood (DHU A-TVB), Department of Physiology, AP-HP, Henri Mondor Hospital, Créteil, France;
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France; Département Hospitalo-Universitairé Ageing Thorax-Vessels Blood (DHU A-TVB), Department of Physiology, AP-HP, Henri Mondor Hospital, Créteil, France;
authors.forename: Geneviève
authors.initials: G
authors.lastname: Derumeaux
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France; DHU A-TVB, Department of Cardiology, AP-HP, Henri Mondor Hospital, Créteil, France; Department of Cardiology, Poitiers University Hospital, F-86000, Poitiers, France barnabas.gellen@hmn.aphp.fr.
authors.forename: Barnabas
authors.identifier: http://orcid.org/0000-0002-1128-2985
authors.initials: B
authors.lastname: Gellen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005838:Genotype; D006342:Heart Rupture, Post-Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D013997:Time Factors; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D014945:Wound Healing
chemical_list: D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; C064658:RAG-1 protein; C033668:calpastatin; D002154:Calpain
keywords: calpain; calpastatin; cardiac rupture; inflammation; lymphocytes; macrophages; myocardial infarction; scar healing