Journal article
Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction
Journal of the American Heart Association, Vol.2(5), pp.e000301-e000301
09/19/2013
DOI: 10.1161/JAHA.113.000301
PMCID: PMC3835233
PMID: 24052497
Abstract
Increased glucose transporter 1 (GLUT1) expression and glucose utilization that accompany pressure overload-induced hypertrophy (POH) are believed to be cardioprotective. Moreover, it has been shown that lifelong transgenic overexpression of GLUT1 in the heart prevents cardiac dysfunction after aortic constriction. The relevance of this model to clinical practice is unclear because of the life-long duration of increased glucose metabolism. Therefore, we sought to determine if a short-term increase in GLUT1-mediated myocardial glucose uptake would still confer cardioprotection if overexpression occurred at the onset of POH.
Mice with cardiomyocyte-specific inducible overexpression of a hemagglutinin (HA)-tagged GLUT1 transgene (G1HA) and their controls (Cont) were subjected to transverse aortic constriction (TAC) 2 days after transgene induction with doxycycline (DOX). Analysis was performed 4 weeks after TAC. Mitochondrial function, adenosine triphosphate (ATP) synthesis, and mRNA expression of oxidative phosphorylation (OXPHOS) genes were reduced in Cont mice, but were maintained in concert with increased glucose utilization in G1HA following TAC. Despite attenuated adverse remodeling in G1HA relative to control TAC mice, cardiac hypertrophy was exacerbated in these mice, and positive dP/dt (in vivo) and cardiac power (ex vivo) were equivalently decreased in Cont and G1HA TAC mice compared to shams, consistent with left ventricular dysfunction. O-GlcNAcylation of Ca2+ cycling proteins was increased in G1HA TAC hearts.
Short-term cardiac specific induction of GLUT1 at the onset of POH preserves mitochondrial function and attenuates pathological remodeling, but exacerbates the hypertrophic phenotype and is insufficient to prevent POH-induced cardiac contractile dysfunction, possibly due to impaired calcium cycling.
Details
- Title: Subtitle
- Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction
- Creators
- Renata O Pereira - Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UTAdam R WendeCurtis OlsenJamie SotoTenley RawlingsYi ZhuSteven M AndersonE Dale Abel
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.2(5), pp.e000301-e000301
- DOI
- 10.1161/JAHA.113.000301
- PMID
- 24052497
- PMCID
- PMC3835233
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- England
- Grant note
- R01 CA 138482 / NCI NIH HHS 5T32 HL007576 / NHLBI NIH HHS T32 HL007576 / NHLBI NIH HHS R01 CA138482 / NCI NIH HHS R01 DK092065 / NIDDK NIH HHS U54 HL112311 / NHLBI NIH HHS U01 HL087947 / NHLBI NIH HHS P01 HD038129 / NICHD NIH HHS R01DK092065 / NIDDK NIH HHS P01 HD 038129 / NICHD NIH HHS
- Language
- English
- Date published
- 09/19/2013
- 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
- 9984024407902771
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