title: Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes.
abstract: OBJECTIVE
  Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF.
  
  
  RESULTS
  To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two-photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down-regulated compared with these from sham-operated animals, and the mitochondrial network structure altered.
  
  
  CONCLUSIONS
  The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kah Yong
authors.initials: KY
authors.lastname: Goh
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Hong
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA lfzhou@uab.edu.
authors.forename: Lufang
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006333:Heart Failure / Q000503:physiopathology*; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species
keywords: Excitability; Heart failure; Mitochondrial network; Mitofusin protein; ROS-induced-ROS release