Abstract 14617: Cardiac Sodium Glucose Co-Transporter 1(SGLT1) Overexpression Causes Reversible Cardiac Hypertrophy, Fibrosis and Left Ventricular Dysfunction in Mice
OBJECTIVES: We have reported increases in cardiac SGLT1 expression in human cardiomyopathies. The significance of an increase in SGLT1 expression on cardiac morphology and function is unknown. We constructed a conditional transgenic murine model and examined the effect of SGLT1 overexpression on the heart.
METHODS: Cardiac specific tet-off transgenic mice conditionally overexpressing cardiac SGLT1 were placed in three groups after weaning: continued doxycylcine (TGSGLT-OFF); doxycycline withdrawal (TGSGLT1-ON); and withdrawal of doxyclyine at ages 4-10 weeks followed by resumption at 10-20 weeks (TGSGLT1-ON/OFF). Echocardiography was performed at 7, 10 and 20 weeks. Mice hearts were harvested at 10 and 20 weeks of age for biochemical and histological analysis.
RESULTS: At 7 weeks, TGSGLT1-ON showed an increase in fractional shortening (FS) relative to wildtype (WT) littermates (73±1% vs 54±1%, P<0.001). At 20 weeks, TGSGLT1-ON relative to WT showed a decrease in FS (36±6 vs 56±5%, P<0.05), an increase end diastolic diameter (4.73±0.42 vs 3.04±0.19 mm, P<0.005), an increase in heart to body weight ratio (6.18±1.03 vs 3.28±0.09 mg/g, P<0.05), and an increase in markers of cardiac hypertrophy (6.3-fold increased Nppa1 expression, P<0.005; 2.1-fold increased Nppb1 expression, P<0.05). On histology, TGSGLT1-ON showed myocyte hypertrophy and increased interstitial fibrosis. Quantitative PCR showed a 2.1-fold increase in procollagen-1 (P<0.05) in 20 week old TGSGLT1-ON relative to WT. Twenty-week-old TGSGLT1-ON/OFF relative to 10-week-old TGSGLT1-ON had improved FS (57±6 vs 35±5%, P<0.01), reduced heart to body weight ratio (3.70±0.24 vs 5.53±0.13, P<0.001) and decreased myocyte hypertrophy. There were no significant differences in the heart to body weight ratio or echocardiographic parameters in TGSGLT1-ON/OFF relative WT at 20 weeks.
CONCLUSION: Cardiac overexpression of SGLT1 initially enhances cardiac function, but ultimately leads to cardiac hypertrophy, fibrosis, and dysfunction. These deleterious effects are reversible by suppression of SGLT1 expression. Chronic upregulation of SGLT1 may represent a maladaptive pathway in human heart disease.
- © 2013 by American Heart Association, Inc.