SMIT1 promotes cardiac hypertrophy and fibrosis; its absence protects against pressure overload-induced left ventricular remodelling in mice.
Does SMIT1 deficiency prevent cardiac hypertrophy and fibrosis in a mouse model of pressure overload?
SMIT1 deficiency protects against pressure overload-induced left ventricular remodeling, highlighting SMIT1 inhibition as a potential therapeutic target for heart failure.
Absolute Event Rate: 0% vs 0%
Abstract Introduction Our recent findings identify myo-inositol as a novel metabolite consistently elevated in patients with heart failure. It is specifically transported by the sodium/myo-inositol co-transporter-1 (SMIT1), a member of the sodium-glucose co-transporter (SGLT) family expressed in the heart. However, the underlying mechanisms by which myo-inositol and SMIT1 contribute to heart failure remain unclear. We aimed to determine the role of SMIT1 in left ventricular remodelling and its involvement in the progression to heart failure. Methods We used a model of pressure overload induced by transverse aortic constriction in wild type (WT) and SMIT1 deficient (Smit1-/-) mice. Cardiac structure and function were evaluated using contrast-enhanced microfocus computed tomography and echocardiography. The contribution of SMIT1 to molecular changes was assessed using immunoblotting, histological staining, and RNA-sequencing. In addition, we used primary cultures of adult mouse, neonatal and adult rat ventricular myocytes to investigate the molecular pathways influenced by SMIT1. Results We found that aortic banding fails to induce systolic dysfunction, cardiac hypertrophy and fibrosis in Smit1-/- mice, in contrast to WT controls. SMIT1 expression promotes cardiomyocytes hypertrophy through activation of the IP3/Ca++ signalling. Transcriptomic analysis revealed significant alteration in calcium effectors, including Carabin, a protein that inhibits the calcineurin/NFAT and Ras/ERK1/2 pathways. Accordingly, we demonstrated that Carabin is a SMIT1 downstream key mediator of the transcriptional reprogramming driving cardiac hypertrophy. Conclusions This work establishes SMIT1 as a critical driver of hypertrophy via calcium-dependent pro-hypertrophic signalling. The absence of SMIT1 protects against pressure overload-induced left ventricular remodelling, highlighting SMIT1 inhibition as a potential therapeutic target for preventing or treating pathological hypertrophy and heart failure.
Marino et al. (Sun,) reported a other. SMIT1 promotes cardiac hypertrophy and fibrosis; its absence protects against pressure overload-induced left ventricular remodelling in mice.