title: Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy.
abstract: Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by β-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity.
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: B Cicero
authors.initials: BC
authors.lastname: Willis
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: Ayleen
authors.initials: A
authors.lastname: Salazar-Cantú
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Silva-Platas
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: Evaristo
authors.initials: E
authors.lastname: Fernández-Sada
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: César A
authors.initials: CA
authors.lastname: Villegas
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rios-Argaiz
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: Pilar
authors.initials: P
authors.lastname: González-Serrano
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Sánchez
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Guerrero-Beltrán
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and.
authors.forename: Noemí
authors.initials: N
authors.lastname: García
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Torre-Amione
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and.
authors.forename: Gerardo J
authors.identifier: http://orcid.org/0000-0003-4731-3293
authors.initials: GJ
authors.lastname: García-Rivas
authors.affiliation: Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and altamirano@itesm.mx.
authors.forename: Julio
authors.initials: J
authors.lastname: Altamirano
mesh_terms: D000322:Adrenergic Agonists / Q000633:toxicity; D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000322:Adrenergic Agonists; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
keywords: calcium signaling; cardiac dysfunction; isoproterenol; mitochondrial dysfunction; takotsubo cardiomyopathy