Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice

Mohun Ramratnam; Ravi K Sharma; Stephen D'Auria; So Jung Lee; David Wang; Xue Yin N Huang; Ferhaan Ahmad

doi:10.1161/JAHA.114.000899

Back

Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice

Journal article

Open access

Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice

Mohun Ramratnam, Ravi K Sharma, Stephen D'Auria, So Jung Lee, David Wang, Xue Yin N Huang and Ferhaan Ahmad

Journal of the American Heart Association, Vol.3(4), e000899

08/04/2014

DOI: 10.1161/JAHA.114.000899

PMCID: PMC4310371

PMID: 25092788

Files and links (1)

url

https://doi.org/10.1161/JAHA.114.000899View

Published (Version of record) Open Access

Abstract

The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function. Transgenic mice with cardiomyocyte-specific overexpression of human T400N mutant PRKAG2 cDNA (TG(T400N)) and transgenic mice with cardiomyocyte-specific RNA interference knockdown of SGLT1 (TG(SGLT1-DOWN)) were crossed to produce double-transgenic mice (TG(T400N)/TG(SGLT1-DOWN)). Tet-off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TG(SGLT-ON)). Relative to TG(T400N) mice, TG(T400N)/TG(SGLT1-DOWN) mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P<0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TG(T400N)/TG(SGLT1-DOWN) mice had less left ventricular dilation at age 12 weeks compared to TG(T400N) mice. Relative to wildtype (WT) mice, TG(SGLT1-ON) mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TG(SGLT1-ON) mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TG(SGLT1-ON/OFF)), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure. Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte-specific transgenic knockdown of a target gene.

Glycogen Storage Disease Type IIb - genetics

Hypertrophy, Left Ventricular - metabolism

Mice, Transgenic

RNA, Messenger - metabolism

Glycogen Storage Disease Type IIb - metabolism

Sodium-Glucose Transporter 1 - genetics

Ventricular Dysfunction, Left - metabolism

Cardiomyopathies - genetics

Animals

Hypertrophy, Left Ventricular - genetics

Ventricular Dysfunction, Left - genetics

Cardiomyopathies - metabolism

Glucose - metabolism

Mice

AMP-Activated Protein Kinases - genetics

Disease Models, Animal

Details

Title: Subtitle: Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice
Creators: Mohun Ramratnam - Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI (M.R.) UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.)
Ravi K Sharma - UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.)
Stephen D'Auria - UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.)
So Jung Lee - UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.)
David Wang - University of Pittsburgh
Xue Yin N Huang - UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.)
Ferhaan Ahmad - UPMC Heart and Vascular Institute and Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (M.R., R.K.S., S.A., S.J.L., D.W., X.Y.N.H., F.A.) Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA (F.A.) Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (F.A.)
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.3(4), e000899
DOI: 10.1161/JAHA.114.000899
PMID: 25092788
PMCID: PMC4310371
NLM abbreviation: J Am Heart Assoc
ISSN: 2047-9980
eISSN: 2047-9980
Publisher: England
Grant note: U01 HL108642 / NHLBI NIH HHS R21 HL109812 / NHLBI NIH HHS
Language: English
Date published: 08/04/2014
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025364102771

Metrics

19 Record Views

63 Times Cited - Web of Science

See more details