title: Na+/Ca2+exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models.
abstract: Ca2+-handling disturbances play an important role in the genesis of myocardial ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) is a powerful strategy to induce tolerance against subsequent ischemic episodes. IPC signaling pathways may be triggered by Ca2+ion. Since Na+/Ca2+exchanger 1 (NCX1) participates in modulating intracellular Ca2+homeostasis, here we further defined its role in I/R and investigated its potential involvement in IPC-induced cardioprotection. In isolated ventricular cardiomyocytes, perfused rat heart and H9c2 cardiomyoblasts, I/R produced a significant cell injury, assessed by measuring extracellular lactate dehydrogenase (LDH) and, for the whole heart, also by estimating myocardial infarct size area. Characterization of cell death revealed the involvement of apoptotic processes. Interestingly, I/R challenge induced NCX1 protein upregulation. In NCX1-transfected H9c2 cells, exchanger protein upregulation was accompanied by an increase in its reverse mode activity. The effects of I/R on extracellular LDH and infarct size area were drastically reduced by 1μM SN-6, a selective NCX1 inhibitor. Moreover, SN-6 also prevented I/R-induced increase of NCX1 reverse-mode activity and protein upregulation. These results suggested a deleterious role of NCX1 in I/R-induced cell damage. In both isolated cardiomyocytes and perfused heart, IPC followed by I/R afforded cardioprotection, reducing extracellular LDH release and limiting ischemic area extent. Interestingly, NCX1 blockade (1μM SN-6) completely abolished IPC protection against I/R, leading to exacerbation of cell injury, massive infarct size area and restoration of NCX1 protein expression. These findings suggest that NCX1 is deleterious in I/R, whereas it may be beneficial in promoting IPC-induced cardioprotection.
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: p.castaldo@univpm.it.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Castaldo
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: m.l.macri@univpm.it.
authors.forename: Maria Loredana
authors.initials: ML
authors.lastname: Macrì
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: v.lariccia@univpm.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lariccia
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: a.matteucci@univpm.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Matteucci
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: maiolinomarta.mm@gmail.com.
authors.forename: Marta
authors.initials: M
authors.lastname: Maiolino
authors.affiliation: Department of Health Sciences, University "Magna Graecia", Viale Europa-Localitá Germaneto, 88100 Catanzaro, Italy. Electronic address: gratteri@unicz.it.
authors.forename: Santo
authors.initials: S
authors.lastname: Gratteri
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: s.amoroso@univpm.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Amoroso
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy. Electronic address: s.magi@univpm.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Magi
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005110:Extracellular Space / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D001593:Benzyl Compounds; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; C110374:sodium-calcium exchanger 1; D007770:L-Lactate Dehydrogenase
keywords: Calcium; Cardioprotection; Heart; Ischemia/reperfusion; NCX1; Preconditioning