title: Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes.
abstract: OBJECTIVE
  Obesity and diabetes mellitus type 2 (DM2) frequently coexist and increase the propensity of cardiovascular dysfunction by numerous mechanisms. Chief among them are oxidative stress and Ca(2+) dysregulation, and both are inducers of the mitochondrial permeability transition pore (MPTP). Nevertheless, it is unknown whether MPTP formation is triggered in DM2 animals, and thereby contributing to cardiac dysfunction. We assessed MPTP sensitivity and reactive oxygen species production in cardiac mitochondria, as well as cytosolic Ca(2+) handling in ventricular myocytes from rats with DM2.
  
  
  METHODS
  Male Zucker Fa/fa rats (Fa/fa) 32weeks old presenting DM2, concentric hypertrophy, and diastolic dysfunction were used. MPTP formation was evaluated in isolated mitochondria and Ca(2+) handling in ventricular myocytes, by spectrophotometric and confocal microscope techniques, respectively.
  
  
  RESULTS
  We found that the systolic Ca(2+) transient relaxation was ~40% slower, while mitochondrial H2O2 production increased by ~6-fold. MPTP opening in isolated mitochondria from Fa/fa (mFa/fa) was more sensitive to Ca(2+) than in mitochondria from lean rats (mLean), and correlated with increased thiol group exposure. The mFa/fa showed decreased oxidative phosphorylation capacity. The ATP content decreased in myocytes, while the PCr/ATP ratio remained unchanged and caspase 9 activity largely increased in myocytes from Fa/fa animals.
  
  
  CONCLUSIONS
  Our results showed that oxidative stress and diastolic Ca(2+) dysregulation increased MPTP sensitivity leading to mitochondrial dysfunction and apoptosis. Mitochondrial dysfunction could compromise ATP synthesis, and lower ATP could be linked to decreased SERCA2 activity, which might underlie diastolic dysfunction. Prolonged Ca(2+) transients might further exacerbate mitochondrial dysfunction.
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Adriana
authors.initials: A
authors.lastname: Riojas-Hernández
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Judith
authors.initials: J
authors.lastname: Bernal-Ramírez
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez-Mier
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Flor E
authors.initials: FE
authors.lastname: Morales-Marroquín
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Elvia M
authors.initials: EM
authors.lastname: Domínguez-Barragán
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Cuauhtémoc
authors.initials: C
authors.lastname: Borja-Villa
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México.
authors.forename: Irais
authors.initials: I
authors.lastname: Rivera-Álvarez
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México; Centro de Investigación Básica y de Transferencia, Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza García, NL Mexico.
authors.forename: Gerardo
authors.initials: G
authors.lastname: García-Rivas
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México; Centro de Investigación Básica y de Transferencia, Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza García, NL Mexico.
authors.forename: Julio
authors.initials: J
authors.lastname: Altamirano
authors.affiliation: Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México; Centro de Investigación Básica y de Transferencia, Hospital Zambrano Hellion, Tecnológico de Monterrey, San Pedro Garza García, NL Mexico. Electronic address: garcianr@itesm.mx.
authors.forename: Noemí
authors.initials: N
authors.lastname: García
mesh_terms: D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives / Q000378:metabolism; D020013:Calcium Signaling; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D006331:Heart Diseases / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010539:Permeability; D051381:Rats; D011924:Rats, Zucker; D014463:Ultrasonography
chemical_list: D020738:Leptin; D008055:Lipids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001278:Atractyloside; D000226:Mitochondrial ADP, ATP Translocases; C003853:carboxyatractyloside
keywords: Calcium; Cardiovascular disease; Diastolic dysfunction; Mitochondrial dysfunction; Obesity