Open AccessTransgenic Knockdown of Cardiac Sodium/Glucose Cotransporter 1 ( SGLT 1) Attenuates PRKAG 2 Cardiomyopathy, Whereas Transgenic Overexpression of Cardiac SGLT 1 Causes Pathologic Hypertrophy and Dysfunction in Mice
Author(s) -
Ramratnam Mohun,
Sharma Ravi K.,
D'Auria Stephen,
Lee So Jung,
Wang David,
Huang Xue Yin N.,
Ahmad Ferhaan
Publication year - 2014
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.000899
Subject(s) - medicine , cardiomyopathy , endocrinology , genetically modified mouse , transgene , gene knockdown , diabetic cardiomyopathy , muscle hypertrophy , glycogen , heart failure , myocyte , cardiac function curve , cardiology , biology , biochemistry , apoptosis , gene
Background The expression of a novel cardiac glucose transporter, SGLT 1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG 2 . We sought to determine the role of SGLT 1 in the pathogenesis of PRKAG 2 cardiomyopathy and its role in cardiac structure and function. Methods and Results 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. Conclusions Cardiac knockdown of SGLT 1 in a murine model of PRKAG 2 cardiomyopathy attenuates the disease phenotype, implicating SGLT 1 in the pathogenesis. Overexpression of SGLT 1 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.