Document Detail


Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction.
MedLine Citation:
PMID:  19249310     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Diabetes increases mortality and accelerates left ventricular (LV) dysfunction following myocardial infarction (MI). This study sought to determine the impact of impaired myocardial insulin signaling, in the absence of diabetes, on the development of LV dysfunction following MI. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wildtype (WT) mice were subjected to proximal left coronary artery ligation (MI) and followed for 14 days. Despite equivalent infarct size, mortality was increased in CIRKO-MI vs. WT-MI mice (68% vs. 40%, respectively). In surviving mice, LV ejection fraction and dP/dt were reduced by >40% in CIRKO-MI vs. WT-MI. Relative to shams, isometric developed tension in LV papillary muscles increased in WT-MI but not in CIRKO-MI. Time to peak tension and relaxation times were prolonged in CIRKO-MI vs. WT-MI suggesting impaired, load-independent myocardial contractile function. To elucidate mechanisms for impaired LV contractility, mitochondrial function was examined in permeabilized cardiac fibers. Whereas maximal ADP-stimulated mitochondrial O(2) consumption rates (V(ADP)) with palmitoyl carnitine were unchanged in WT-MI mice relative to sham-operated animals, V(ADP) was significantly reduced in CIRKO-MI (13.17+/-0.94 vs. 9.14+/-0.88 nmol O(2)/min/mgdw, p<0.05). Relative to WT-MI, expression levels of GLUT4, PPAR-alpha, SERCA2, and the FA-Oxidation genes MCAD, LCAD, CPT2 and the electron transfer flavoprotein ETFDH were repressed in CIRKO-MI. Thus reduced insulin action in cardiac myocytes accelerates post-MI LV dysfunction, due in part to a rapid decline in mitochondrial FA oxidative capacity, which combined with limited glucose transport capacity that may reduce substrate utilization and availability.
Authors:
Sandra Sena; Ping Hu; Dongfang Zhang; Xiaohui Wang; Benjamin Wayment; Curtis Olsen; Erick Avelar; E Dale Abel; Sheldon E Litwin
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-02-26
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  46     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-15     Completed Date:  2009-08-20     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  910-8     Citation Subset:  IM    
Affiliation:
Division of Endocrinology Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
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MeSH Terms
Descriptor/Qualifier:
Acyl-CoA Dehydrogenase / metabolism
Acyl-CoA Dehydrogenase, Long-Chain / metabolism
Animals
Echocardiography
Fatty Acids / metabolism
Female
Glucose Transporter Type 4 / metabolism
Lipid Metabolism / genetics
Mice
Mice, Knockout
Mitochondria, Heart / metabolism*,  pathology
Myocardial Infarction / metabolism,  physiopathology
Oxygen Consumption
PPAR alpha / metabolism
Polymerase Chain Reaction
Receptor, Insulin / genetics,  physiology*
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Signal Transduction / genetics,  physiology
Grant Support
ID/Acronym/Agency:
HL70070/HL/NHLBI NIH HHS; R01 DK092065-07/DK/NIDDK NIH HHS; R01 HL070070-04/HL/NHLBI NIH HHS; U01 HL087947/HL/NHLBI NIH HHS; U01 HL087947/HL/NHLBI NIH HHS; U01 HL087947-03/HL/NHLBI NIH HHS; U01-HL70525/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Glucose Transporter Type 4; 0/PPAR alpha; 0/Slc2a4 protein, mouse; EC 1.3.99.13/Acyl-CoA Dehydrogenase, Long-Chain; EC 1.3.99.3/Acyl-CoA Dehydrogenase; EC 2.7.10.1/Receptor, Insulin; EC 3.6.3.8/Atp2a2 protein, mouse; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases
Comments/Corrections

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