title: Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation.
abstract: Dexamethasone is a potent and widely used anti-inflammatory and immunosuppressive drug. However, recent evidences suggest that dexamethasone cause pathologic cardiac remodeling, which later impairs cardiac function. The mechanism behind the cardiotoxic effect of dexamethasone is elusive. The present study aimed to verify if dexamethasone-induced cardiotoxicity would be associated with changes in the cardiac net balance of calcium handling protein and calcineurin signaling pathway activation. Wistar rats (~400 g) were treated with dexamethasone (35 µg/g) in drinking water for 15 days. After dexamethasone treatment, we analyzed cardiac function, cardiomyocyte diameter, cardiac fibrosis, and the expression of proteins involved in calcium handling and calcineurin signaling pathway. Dexamethasone-treated rats showed several cardiovascular abnormalities, including elevated blood pressure, diastolic dysfunction, cardiac fibrosis, and cardiomyocyte apoptosis. Regarding the expression of proteins involved in calcium handling, dexamethasone increased phosphorylation of phospholamban at threonine 17, reduced protein levels of Na+/Ca2+exchanger, and had no effect on protein expression of Serca2a. Protein levels of NFAT and GATA-4 were increased in both cytoplasmic and nuclear faction. In addition, dexamethasone increased nuclear protein levels of calcineurin. Altogether our findings suggest that dexamethasone causes pathologic cardiac remodeling and diastolic dysfunction, which is associated with impaired calcium handling and calcineurin signaling pathway activation.
authors.affiliation: Biosciences Department, Federal University of Sao Paulo, Silva Jardim, 136-Vl. Mathias, Santos, SP, 11015-020, Brazil.
authors.forename: Fabiana
authors.identifier: http://orcid.org/0000-0002-2842-4716
authors.initials: F
authors.lastname: de Salvi Guimarães
authors.affiliation: Biosciences Department, Federal University of Sao Paulo, Silva Jardim, 136-Vl. Mathias, Santos, SP, 11015-020, Brazil.
authors.forename: Wilson Max Almeida Monteiro
authors.initials: WM
authors.lastname: de Moraes
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Luis Henrique Marchesi
authors.initials: LH
authors.lastname: Bozi
authors.affiliation: Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
authors.forename: Pâmela R
authors.initials: PR
authors.lastname: Souza
authors.affiliation: Cardio-Physiology and Pathophysiology Laboratory, Federal University of Sao Paulo, São Paulo, Brazil.
authors.forename: Ednei Luiz
authors.initials: EL
authors.lastname: Antonio
authors.affiliation: Cardio-Physiology and Pathophysiology Laboratory, Federal University of Sao Paulo, São Paulo, Brazil.|Department of Post-Graduation in Physical Education, São Judas Tadeu University, São Paulo, Brazil.
authors.forename: Danilo Sales
authors.initials: DS
authors.lastname: Bocalini
authors.affiliation: Cardio-Physiology and Pathophysiology Laboratory, Federal University of Sao Paulo, São Paulo, Brazil.
authors.forename: Paulo José Ferreira
authors.initials: PJ
authors.lastname: Tucci
authors.affiliation: Biosciences Department, Federal University of Sao Paulo, Silva Jardim, 136-Vl. Mathias, Santos, SP, 11015-020, Brazil.
authors.forename: Daniel Araki
authors.initials: DA
authors.lastname: Ribeiro
authors.affiliation: School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Patricia Chakur
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Biosciences Department, Federal University of Sao Paulo, Silva Jardim, 136-Vl. Mathias, Santos, SP, 11015-020, Brazil. a.medeiros@unifesp.br.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Medeiros
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003907:Dexamethasone; D019703:Calcineurin
keywords: Calcium homeostasis; Cardiac dysfunction; Cardiac hypertrophy; Glucocorticoids