SMIT1 as a new potential target in heart failure with preserved ejection fraction

• Published in: Archives of cardiovascular diseases 2024-06, Vol.117 (6-7), p.S185-S185
• Main Authors: Baufays, Claire, Marino, Alice, Cumps, Julien, Bertrand, Luc, Horman, Sandrine, Beauloye, Christophe
• Format: Article
• Language: English
• ISSN: 1875-2136; 1875-2128
• DOI: 10.1016/j.acvd.2024.05.049

Heart failure with preserved ejection fraction (HFpEF) is a life-threatening syndrome with limited therapeutic options and poorly understood molecular mechanisms. HFpEF arises in patients with multiple comorbidities, such as obesity and hypertension, which ultimately lead to left ventricular remodeling and diastolic dysfunction. We recently found that plasmatic levels of myo-inositol are particularly elevated in patients with HFpEF, and that its selective transporter SMIT1 favors cardiac hypertrophy and fibrosis following pressure overload, suggesting that the myo-inositol/SMIT1 axis contributes to the development of heart failure. However, the role of SMIT1 in the context of HFpEF remains fully unexplored. Our project aims to evaluate the role of SMIT1 in a murine model of HFpEF. To induce HFpEF, wild type (WT) and SMIT1 knockout (KO) mice were submitted to high fat diet (60% of calories from fat) and NO-synthase inhibitor (N-nitro-L-arginine methyl ester (L-NAME) 0.5g/L in drinking water) for 16weeks. Echocardiographic and hemodynamic (Millar catheter) analyses were performed to assess cardiac phenotype and function. Body weight and glucose homeostasis were monitored over time. Immunohistochemistry analysis was used to evaluate cardiomyocytes hypertrophy and interstitial fibrosis. Pro-inflammatory cytokines mRNA expression was assessed by RT-qPCR on cardiac tissue. The lack of SMIT1 prevents the development of HFpEF-induced cardiac hypertrophy and improves diastolic function when compared to WT mice. After 16weeks of HFpEF regimen, expression of cardiac pro-inflammatory cytokines was augmented in WT mice, while it was significantly decreased in cardiac tissue from littermates lacking SMIT1. Moreover, SMIT1 KO mice display blunted weight gain and insulin resistance compared to WT mice. In a murine model of comorbidity-induced HFpEF, the absence of SMIT1 prevents cardiac hypertrophy, improves diastolic function and myocardial inflammation, and limits weight gain and insulin resistance. Thus, SMIT1 is a key player in the pathophysiology of HFpEF and may represent a new potential therapeutic target.