The SMIT1 Axis: Orchestrating Hypertrophy and Fibrosis Under Pressure

SMIT1 a new driver of cardiac remodelling

Current cardiac research is increasingly focused on identifying strategies to prevent cardiac hypertrophy and fibrosis, two major hallmarks of left ventricular remodelling that drive increased myocardial stiffness and progression towards heart failure. In this context, Marino et al.1 provide compelling evidence identifying sodium/myo-inositol cotransporter 1 (SMIT1) as a previously unrecognized regulator of pathological cardiac remodelling. SMIT1, a membrane protein belonging to the sodium/glucose co-transporter (SGLT) family, mediates the active transport into the cells of myo-inositol via a sodium-dependent gradient. Although expressed in cardiac tissue, its physiological and pathological role remains unclear, especially in the context of heart failure, a condition associated with elevated circulating levels of myo-inositol.2-4 Marino et al. now demonstrate, for the first time, that myo-inositol directly induces cardiomyocyte hypertrophy via an activation of IP3-Ca2+ dependent signaling pathway, an effect critically dependent on SMIT1 expression.

How SMIT1 fuels pathological hypertrophy

Using a global SMIT1 knockout mouse model, the authors established SMIT1 is a key driver of pathological cardiac remodelling. Mechanistically, increased myo-inositol levels enhanced the production of IP3, triggering Ca2+ release from the sarcoplasmic reticulum and elevating intracellular Ca2+ levels. In turn, this activates a pro-hypertrophic signalling cascade, including calcineurin/NFAT and Ras/ERK1/2 pathways, ultimately promoting cardiomyocyte growth, fibrosis, and adverse left ventricular remodelling. Interestingly, SMIT1 deficiency was associated with reduced sarcoplasmic reticulum Ca2+ content. Under stress conditions, such as phenylephrine or pressure overload, this translates into an attenuation of the IP3-Ca2+ dependent transcriptional reprograming and protection against pathological hypertrophy. These findings highlight a critical role for SMIT1 in modulating intracellular calcium dynamics and downstream hypertrophic signalling.

The study is further strengthened by the use of robust experimental approaches, such as transverse aortic constriction (TAC), micro-computed tomography imaging, and primary cardiomyocyte isolation. Transcriptomic analyses comparing WT and SMIT1-deficient TAC-operated hearts revealed significant dysregulation of genes involved in hypertrophy, fibrosis, ions homeostasis, and IP3 signalling. Among these, Tbc1d10c, encoding the protein Carabin, emerged as a key mediator. Carabin is an endogenous inhibitor of the calcineurin/NFAT and Ras/ERK1/2 pathways. Importantly, its expression was preserved in SMIT1-deficient hearts, correlating with reduced activation of hypertrophic signalling. In vitro, SMIT1 deletion upregulated Carabin expression, whereas SMIT1 overexpression suppressed it, reinforcing an inverse relationship between SMIT1 activity and hypertrophic signalling. These findings position Carabin as a central mediator of the protective phenotype observed in the absence of SMIT1.

Beyond cardiomyocytes, SMIT1 is also present in cardiac fibroblasts, suggesting a broader role in regulating cardiac remodelling. However, the lack of cell-type specific conditional knockout models represents an important limitation, preventing precise delineation of the relative contributions of cardiomyocytes and fibroblasts. Furthermore, given the key role of SMIT1 in triggering NOX2 activation and ROS production SMIT1 modulates intracellular Na+ levels and Ca2+,5,6 an indirect impact on mitochondrial activity may be expected to increase ROS generation and oxidative stress, thereby promoting cardiomyocyte dysfunction. 

SMIT a novel potential therapeutic target

These findings also intersect with ongoing efforts to understand the cardioprotective effects of SGLT2 inhibitors (SGLT2i). Originally developed for the treatment of type 2 diabetes mellitus, and included among the “four pillars” of heart failure therapy,7 SGLT2i have been considered the “holy grail” for the substantial benefits in attenuating heart failure symptoms and limiting hospitalizations, independently of glycemic control. However, direct beneficial effects of SGLT2i on the heart remain elusive. Contrarily to SGLT2,8 SMIT1 is expressed in cardiac cells and strictly controls myo-inositol uptake, making it an interesting new potential target for therapeutic intervention.

Overall, Marino et al. identify SMIT1 as a novel and critical contributor to pathological cardiac hypertrophy, acting via IP3-Ca2+-mediated signalling and associated transcriptional changes. The demonstrated link between disrupted myo-inositol metabolism and aberrant calcium signalling represents an important conceptual advance in cardiac remodelling. Their work reshapes current views on cardiac remodelling and points toward novel therapeutic approaches in heart failure.