Document Detail


Anoxic cell core can promote necrotic cell death in cardiomyocytes at physiological extracellular PO2.
MedLine Citation:
PMID:  18424639     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The physical law of diffusion imposes O2 concentration gradients from the plasma membrane to the center of the cell. The present study was undertaken to determine how such intracellular radial gradients of O2 affect the fate of isolated single cardiomyocytes. In single rat cardiomyocytes, mitochondrial respiration was moderately elevated by an oxidative phosphorylation uncoupler to augment the intracellular O2 gradient. At physiological extracellular O2 levels (2-5%), decreases in myoglobin O2 saturation and increases in NADH fluorescence at the center of the cell were imaged (anoxic cell core) while the mitochondrial membrane potential (DeltaPsim) and ATP levels at the anoxic cell core were relatively sustained. In contrast, treatment with 0.5 mM iodoacetamide (IA) to inhibit creatine kinase (CK) resulted in depletion of both DeltaPsim and ATP at the anoxic cell core. Even at normal extracellular Po2, actively respiring cardiomyocytes developed rigor contracture followed by necrotic cell death. Furthermore, such rigor was remarkably accelerated by IA, whereas cell injury was perfectly rescued by mitochondrial F1Fo inhibition by oligomycin. These results suggest that increases in radial gradients of O2 potentially promote cell death through the reverse action of F1Fo in mitochondria located at the anoxic cell core. However, in the intact cardiomyocyte, the CK-mediated energy flux from the subsarcolemmal space may sustain DeltaPsim at the cell core, thus avoiding uncontrolled consumption of ATP that can lead to necrotic cell death. Mitochondria at the anoxic core can cause necrotic cell death in cardiomyocytes at physiological extracellular Po2.
Authors:
Eiji Takahashi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-04-18
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  294     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-09     Completed Date:  2008-08-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2507-15     Citation Subset:  IM    
Affiliation:
General Medical Education and Department of Physiology, Yamagata Univ. School of Medicine, Yamagata 990-9585, Japan. eiji@med.id.yamagata-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Cell Hypoxia
Cell Respiration
Cell Survival
Creatine Kinase / antagonists & inhibitors,  metabolism
Diffusion
Enzyme Inhibitors / pharmacology
Iodoacetamide / pharmacology
Membrane Potential, Mitochondrial
Mitochondria, Heart / drug effects,  enzymology,  metabolism*,  pathology
Myocytes, Cardiac / drug effects,  enzymology,  metabolism*,  pathology
Myoglobin / metabolism
NAD / metabolism
Necrosis
Oligomycins / pharmacology
Oxidative Phosphorylation
Oxygen / metabolism*
Phosphocreatine / metabolism
Rats
Rats, Sprague-Dawley
Time Factors
Uncoupling Agents / pharmacology
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Myoglobin; 0/Oligomycins; 0/Uncoupling Agents; 144-48-9/Iodoacetamide; 53-84-9/NAD; 56-65-5/Adenosine Triphosphate; 67-07-2/Phosphocreatine; 7782-44-7/Oxygen; EC 2.7.3.2/Creatine Kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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