Mice lacking SMIT1 were protected from pressure overload-induced systolic dysfunction, fibrosis, and hypertrophy due to reduced IP3/Ca2+ pro-hypertrophic signaling.
Does genetic deletion of SMIT1 prevent pressure overload-induced cardiac hypertrophy and fibrosis in mice?
SMIT1 deletion protects against pressure overload-induced cardiac hypertrophy and fibrosis, identifying it as a potential therapeutic target for preventing or treating heart failure.
Tasa de eventos absoluta: 0% vs 0%
Abstract 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 signalling, 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 remodelling 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 favours intracellular myo-inositol and Na+ entry, leading to inositol 1,4,5-trisphosphate (IP3)- and Ca2+-dependent pro-hypertrophic signalling. Following haemodynamic stress, deletion of SMIT1 significantly altered IP3/calcium effectors, including Carabin, which modulates cardiac hypertrophy through inhibition of the calcineurin/nuclear factor of activated T-cell and Ras/ERK1/2 pathways. Conclusion 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 IP3/Ca2+-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.
Marino et al. (Fri,) reported a other. Mice lacking SMIT1 were protected from pressure overload-induced systolic dysfunction, fibrosis, and hypertrophy due to reduced IP3/Ca2+ pro-hypertrophic signaling.