title: Tissue kallikrein is required for the cardioprotective effect of cyclosporin A in myocardial ischemia in the mouse.
abstract: Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA. Homozygote and heterozygote TK deficient mice (TK(-/-), TK(+/-)) and wild type littermates (TK(+/+)) were subjected to cardiac ischemia-reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK(+/+) mice but had no effect in TK(+/-) and TK(-/-) mice. Cardiac mitochondria isolated from TK(-/-) mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK(+/+) mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD. Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France; Université de Lorraine, Nancy, France.
authors.forename: G
authors.initials: G
authors.lastname: Youcef
authors.affiliation: Inserm U 1060-CarMeN & Service d'Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Belaidi
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Waeckel
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Fazal
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Clemessy
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: M P
authors.initials: MP
authors.lastname: Vincent
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Zadigue
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Richer
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.affiliation: Inserm U 1060-CarMeN & Service d'Explorations Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Ovize
authors.affiliation: Inserm UMR 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Paris, France; Université Pierre et Marie Curie, Paris, France; Université de Lorraine, Nancy, France; Inserm UMRS 1116, faculté de médecine de Nancy-Brabois, Vandoeuvre-lès-Nancy, France; Inserm CIC-1433, Institut du Cœur et des Vaisseaux Louis Mathieu, Vandoeuvre-lès-Nancy, France; CHRU Nancy Brabois, Vandoeuvre-lès-Nancy, France. Electronic address: anne.pizard@inserm.fr.
authors.forename: A
authors.initials: A
authors.lastname: Pizard
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D057775:Ischemic Postconditioning; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation; D051381:Rats; D015398:Signal Transduction; D020840:Tissue Kallikreins / Q000172:deficiency / Q000235:genetics*; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; C494763:Vdac1 protein, mouse; D016572:Cyclosporine; D050995:Voltage-Dependent Anion Channel 1; D020840:Tissue Kallikreins; D021983:Cyclophilins
keywords: Cardiac ischemia–reperfusion; Cyclosporin A; Mitochondria; Tissue kallikrein