Kah Yong Goh1, Jing Qu1, Huixian Hong1, Ting Liu2, Louis J Dell'Italia1, Yong Wu3, Brian O'Rourke2, Lufang Zhou4. 1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA. 2. Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, USA. 3. Division of Molecular Medicine, Department of Anesthesiology, University of California at Los Angeles, Los Angeles, CA, USA. 4. 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.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: H Tsutsui; T Ide; S Hayashidani; N Suematsu; H Utsumi; R Nakamura; K Egashira; A Takeshita Journal: Cardiovasc Res Date: 2001-01 Impact factor: 10.787
Authors: Camila Lopez-Crisosto; Christian Pennanen; Cesar Vasquez-Trincado; Pablo E Morales; Roberto Bravo-Sagua; Andrew F G Quest; Mario Chiong; Sergio Lavandero Journal: Nat Rev Cardiol Date: 2017-03-09 Impact factor: 32.419