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

• DOI: 10.1161/jaha.114.000899
• Publication Date: 2014-08-05T02:01:45Z
• Authors: Mohun Ramratnam; Ravi K. Sharma; Stephen D'Auria; So Jung Lee; David Wang; Xue Yin N. Huang; Ferhaan Ahmad
• Keywords: Diabetic Cardiomyopathy; Cardiac Dysfunction

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