title: Impaired ADP channeling to mitochondria and elevated reactive oxygen species in hypertensive hearts.
abstract: Systemic hypertension initially promotes a compensatory cardiac hypertrophy, yet it progresses to heart failure (HF), and energetic deficits appear to be central to this failure. However, the transfer of energy between the mitochondria and the myofibrils is not often considered as part of the energetic equation. We compared hearts from old spontaneously hypertensive rats (SHRs) and normotensive Wistar controls. SHR hearts showed a 35% depression in mitochondrial function, yet produced at least double the amount of reactive oxygen species (ROS) in all respiration states in left ventricular (LV) homogenates. To test the connectivity between mitochondria and myofibrils, respiration was further tested in situ with LV permeabilized fibers by addition of multiple substrates and ATP, which requires hydrolysis to mediate oxidative phosphorylation. By trapping ADP using a pyruvate kinase enzyme system, we tested ADP channeling towards mitochondria, and this suppressed respiration and elevated ROS production more in the SHR fibers. The ADP-trapped state was also less relieved on creatine addition, likely reflecting the 30% depression in total CK activity in the SHR heart fibers. Confocal imaging identified a 34% longer distance between the centers of myofibril to mitochondria in the SHR hearts, which increases transverse metabolite diffusion distances (e.g., for ATP, ADP, and creatine phosphate). We propose that impaired connectivity between mitochondria and myofibrils may contribute to elevated ROS production. Impaired energy exchange could be the result of ultrastructural changes that occur with hypertrophy in this model of hypertension.
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand; and Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand;
authors.forename: Amelia S C
authors.initials: AS
authors.lastname: Power
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand;
authors.forename: Toan
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand; and.
authors.forename: Denis S
authors.initials: DS
authors.lastname: Loiselle
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand;
authors.forename: David H
authors.initials: DH
authors.lastname: Crossman
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand;
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Ward
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand; and Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand a.hickey@auckland.ac.nz.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D003401:Creatine / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D003401:Creatine
keywords: creatine shuttle; hypertrophy; mitochondria; oxidative phosphorylation; reactive oxygen species