Document Detail


Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.
MedLine Citation:
PMID:  18456722     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.
Authors:
Qianwen Wang; Rajakumar V Donthi; Jianxun Wang; Alex J Lange; Lewis J Watson; Steven P Jones; Paul N Epstein
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-05-02
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:  2011-05-03    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2889-97     Citation Subset:  IM    
Affiliation:
Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Hypoxia
Disease Models, Animal
Glycolysis*
Hypertrophy
Insulin / metabolism
Male
Mice
Mice, Transgenic
Muscle Contraction
Mutation*
Myocardial Infarction / enzymology
Myocardial Reperfusion Injury / enzymology*,  pathology
Myocardium / enzymology*,  pathology
Myocytes, Cardiac / enzymology
Oxidation-Reduction
Palmitic Acid / metabolism
Phosphofructokinase-2 / genetics,  metabolism*
Time Factors
Up-Regulation
Grant Support
ID/Acronym/Agency:
DK-073586/DK/NIDDK NIH HHS; HL-62892/HL/NHLBI NIH HHS; HL-83320/HL/NHLBI NIH HHS; R01 HL094419-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
11061-68-0/Insulin; 57-10-3/Palmitic Acid; EC 2.7.1.105/Phosphofructokinase-2

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


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