Sodium myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis in pressure overloaded mouse hearts
Sodium myo-inositol cotransporter-1 (SMIT1) belongs to the sodium-glucose cotransporter family and accounts for intracellular accumulation of myo-inositol. SMIT1 is expressed in the heart, where its function remains unknown. Here, we demonstrate the contribution of SMIT1 to pathological hypertrophic cardiac remodeling and the progression to heart failure, using a mouse model of pressure overload induced by transverse aortic constriction. We found that aortic banding failed to induce systolic dysfunction, cardiac hypertrophy and fibrosis in mice lacking SMIT1 (Smit1-/-), in contrast to wild type controls. SMIT1 genetic deletion reduced cardiac O-GlcNAcylation, which normally increases following hemodynamic stress, and restored ions homeostasis preventing the resulting pro-hypertrophic transcriptional reprogramming. This work provides important insights into the role of SMIT1 at the onset of heart failure, opening new avenues of potential therapeutic strategy to prevent or treat pathological hypertrophy and heart failure. Overall design: We subjected five WT and five Smit1-/- mice to transverse aortic contriction (TAC) surgery. After two weeks post TAC, RNA was extracted from mouse hearts for RNA seq, to investigate  what genes are differentially expressed and what potential pathways could be involved in pressure overload. We then performed gene expression profiling analysis using data obtained from RNAseq to compare WT vs SMIT1-/- mice