Mechanosensitive BMP4 and the IL-33/sST2 Axis in Cardiac Remodeling Associated with Diet-Induced Obesity in Mice

Introduction: Obesity, particularly when induced by chronic consumption of a high-fat diet, is closely associated with adverse cardiac remodeling and increased cardiovascular risk. In this study, we explored the role of Bone Morphogenetic Protein 4 (BMP4), a mechano-sensitive cytokine in the hearts of mice with diet-induced obesity (DIO) and its possible association to the IL-33/sST2 signaling axis, a well-known mechanism involved in maladaptive heart remodeling. Methods: Twelve 6-week-old male C57BL/6N DIO-mice (Charles River Laboratories, Calco, Italy) were divided into 2 groups and fed for 20 weeks as follows: 1) normal chow diet (10% fat, CTR), and 2) high-fat diet (60% fat). At the age of 26 weeks (human beings age matched at 20 to 30 years) the mice were sacrificed through exposure to atmosphere saturation of carbon dioxide for 15 minutes. Hearts were collected and subdivided into 2 parts; heart halves were immediately snap-frozen in liquid nitrogen and stored at −80°C until genomic analysis and proteomic analysis. The Italian Ministry of Health approved all animal procedures (Number 5AD83.N.G1Q). Results: Our results revealed a significant upregulation of BMP4 gene in the myocardium of DIO mice. Elevated BMP4 levels were associated with increased expression of hypertrophic markers (ANP, BNP) and pro-fibrotic genes (TGF-β1, collagen I). Interesting, BMP4 expression directly correlates with IL1RL1 gene, which transduces for sST2, a cardiac maker of maladaptive remodeling. In parallel, we observed an imbalance in the IL-33/sST2 axis: IL-33 expression was markedly decreased, whereas levels of soluble ST2 (sST2), a decoy receptor that neutralizes IL-33, were significantly elevated. This dysregulation was accompanied by enhanced myocardial fibrosis and infiltration of inflammatory cells, as evidenced by increased gene expression of MCP-1 and IL-6. Conclusions: These findings suggest that obesity-induced mechanical and metabolic stress enhances BMP4 signaling and disrupts the IL-33/sST2 cardioprotective pathway, promoting inflammation and structural remodeling of the heart. Understanding these mechanisms may offer novel targets for therapeutic intervention in obesity-related cardiac dysfunction.