Key result
Deletion of SMIT1 protected mice against pressure overload-induced cardiac hypertrophy and fibrosis by reducing O-GlcNAcylation and maintaining Carabin levels.
Why the study?
Plasma myo-inositol is elevated in heart failure, but its role and the role of its transporter SMIT1 in cardiac dysfunction and left ventricular remodeling remain poorly understood.
SMIT1 deletion protects against pressure overload-induced cardiac hypertrophy and fibrosis in mice, suggesting SMIT1 as a potential therapeutic target for heart failure.
SMIT1 may be a novel target to limit HF remodeling; leaves open human translation after this preclinical study.
Aims Recent clinical studies have reported that myo -inositol is consistently elevated in plasma of patients with heart failure (HF), yet its role in cardiac dysfunction remains poorly understood. Myo -inositol is specifically transported into cells by the sodium- myo -inositol co-transporter-1 (SMIT1), a member of the sodium-glucose co-transporter (SGLT) family expressed in the heart. While myo -inositol is essential for phosphoinositide signaling, osmoregulation, and metabolic homeostasis, dysregulation of SMIT1-mediated myo -inositol transport may contribute to key pathological mechanisms in HF. This study aims to elucidate the role of SMIT1 in the failing heart, especially during left ventricular remodeling that precedes it. Methods and results We used a mouse model of pressure overload induced by transverse aortic constriction in wild-type (WT) mice and mice lacking SMIT1 ( Smit1 -/- ), and primary cultured cardiomyocytes. By combining molecular, structural and functional studies, RNA-sequencing, and calcium measurements, we demonstrate the contribution of myo -inositol and SMIT1 to pathological hypertrophy and the progression towards HF. We found that in comparison to WT controls, Smit1 -/- mice were protected against aortic banding induced systolic dysfunction, cardiac fibrosis and hypertrophy. This hypertrophic response was driven by SMIT1 expression in cardiomyocytes, where it favors intracellular myo -inositol and Na + entry, leading to inositol 1,4,5-trisphosphate (IP 3 )- and Ca 2+ -dependent pro-hypertrophic signaling. Following hemodynamic stress, deletion of SMIT1 significantly altered IP 3 /calcium effectors, including Carabin, which modulates cardiac hypertrophy through inhibition of the calcineurin/NFAT and Ras/ERK1/2 pathways. Conclusions This work provides important insights into the role of myo -inositol and SMIT1 in cardiomyocytes. We demonstrate that SMIT1 is a key driver of pathological hypertrophy by inducing an IP 3 /Ca 2+ -dependent pro-hypertrophic transcriptional reprogramming in cardiomyocytes. These findings identify SMIT1 as a promising therapeutic target for preventing or treating pathological cardiac hypertrophy and HF.
No takes yet. Share an insight, caveat, or question.
Marino et al. (2023) studied Cardiac hypertrophy and fibrosis. SMIT1 deletion (Smit1-/-) vs. Wild type (WT) mice was evaluated on Cardiac hypertrophy, fibrosis, and systolic function following pressure overload. Deletion of SMIT1 protected mice against pressure overload-induced cardiac hypertrophy and fibrosis by reducing O-GlcNAcylation and maintaining Carabin levels.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: