The Myo-Inositol/SMIT1 axis as a key regulator of cardiac fibrotic remodelling

Abstract Background/Introduction Elevated plasma myo-inositol levels have emerged as a key metabolic modulator in the pathogenesis of heart failure (HF), with growing evidence linking it to both cardiac dysfunction and fibrotic remodelling (1). Genetic variants in the SLC5A3 locus, which encodes the primary transporter of myo-inositol in the heart, namely sodium-myo-inositol co-transporter 1 (SMIT1), have been associated with increased mortality following myocardial infarction (MI) and a higher risk of coronary artery disease (2), both conditions characterised by extensive fibrotic remodelling. Moreover, in mouse models, deletion of SMIT1 was observed to protect against pressure overload-induced cardiac hypertrophy and fibrosis (3), strengthening the hypothesis of a potential disease-driving mechanism involving the myo-inositol/ SMIT1 axis. Purpose Despite these findings, the specific role of SMIT1, particularly within cardiac fibroblasts, remains poorly understood. To address this, we assessed its contribution to cardiac fibrosis by combining human myocardial data, mouse MI models, and in vitro experiments. Methods and Results Transcriptomic analysis in failing human hearts revealed significantly elevated SMIT1 expression in fibrotic left ventricular tissue, which correlated with numerous genes involved in pro-fibrotic pathways, including TGF-β signalling and extracellular matrix remodelling. Similarly, in mice subjected to permanent left anterior descending artery ligation, SMIT1 expression was increased in the infarcted area alongside other pro-fibrotic markers. Finally, in vitro assays using human cardiac fibroblasts demonstrated that the myo-inositol/SMIT1 axis regulates key fibroblast functions, including proliferation, migration, and myofibroblast differentiation. Consistently, cardiac fibroblasts isolated from SMIT1 knockout mice showed impaired TGF-β responsiveness, reduced myo-differentiation, decreased contractile function, and lowered collagen production. Conclusion Collectively, these findings suggest that SMIT1 contributes to cardiac fibroblast activation and the establishment of myocardial fibrosis (Figure 1) following stress or injury, making the myo-inositol/SMIT1 axis a new potential therapeutic target in HF management.Figure 1For image description, please refer to the figure legend and surrounding text.