Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction

Sandra Sena; Ping Hu; Dongfang Zhang; Xiaohui Wang; Benjamin Wayment; Curtis Olsen; Erick Avelar; E. Dale Abel; Sheldon E Litwin

doi:10.1016/j.yjmcc.2009.02.014

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Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction

Journal article

Peer reviewed

Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction

Sandra Sena, Ping Hu, Dongfang Zhang, Xiaohui Wang, Benjamin Wayment, Curtis Olsen, Erick Avelar, E. Dale Abel and Sheldon E Litwin

Journal of molecular and cellular cardiology, Vol.46(6), pp.910-918

2009

DOI: 10.1016/j.yjmcc.2009.02.014

PMCID: PMC2683200

PMID: 19249310

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https://www.ncbi.nlm.nih.gov/pmc/articles/2683200View

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Abstract

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 d P/d t 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-α, 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.

Myocardial infarction

Energy metabolism

Mitochondria

Fatty acid metabolism

Insulin signaling

Details

Title: Subtitle: Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction
Creators: Sandra Sena - Division of Endocrinology Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, 15 North 2030 East, Bldg. 533, Room 3110, Salt Lake City, UT 84112, USA
Ping Hu - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Dongfang Zhang - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Xiaohui Wang - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Benjamin Wayment - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Curtis Olsen - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Erick Avelar - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
E. Dale Abel - Division of Endocrinology Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, 15 North 2030 East, Bldg. 533, Room 3110, Salt Lake City, UT 84112, USA
Sheldon E Litwin - Division of Cardiology, The University of Utah, Salt Lake City, Utah 84112, USA
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.46(6), pp.910-918
DOI: 10.1016/j.yjmcc.2009.02.014
PMID: 19249310
PMCID: PMC2683200
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100000968, name: American Heart Association; DOI: 10.13039/100000002, name: National Institutes of Health, award: HL70070, U01 HL087947, U01-HL70525; DOI: 10.13039/100000041, name: American Diabetes Association
Language: English
Date published: 2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024408402771

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