Adriana Riojas-Hernández1, Judith Bernal-Ramírez1, David Rodríguez-Mier1, Flor E Morales-Marroquín1, Elvia M Domínguez-Barragán1, Cuauhtémoc Borja-Villa1, Irais Rivera-Álvarez1, Gerardo García-Rivas2, Julio Altamirano2, Noemí García3. 1. Cardiología y Medicina Vascular. Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, NL, México. 2. 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. 3. 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.
Abstract
AIMS: 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. MAIN 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
AIMS: 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. MAIN 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. KEY FINDINGS: 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. SIGNIFICANCE: 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: Aiany C Simões-Alves; Joao H Costa-Silva; Idelfonso B Barros-Junior; Reginaldo C da Silva Filho; Diogo A A Vasconcelos; Hubert Vidal; Béatrice Morio; Mariana P Fernandes Journal: Cells Date: 2019-04-10 Impact factor: 6.600