Inhibition of FABP۴ attenuates cardiac fibrosis through inhibition of NLRP۳ inflammasome activation

Objective(s): Cardiac fibrosis is a key biological process of cardiac remodeling and heart failure. Fatty acid-binding protein ۴ (FABP۴) is a lipid-binding protein that can regulate glucose and lipid homeostasis, and its expression was elevated in heart failure. However, whether FABP۴ is involved in cardiac fibrosis remains unknown. Materials and Methods: The cardiac fibrosis model was established in male C۵۷BL/۶ mice with subcutaneously infused angiotensin II (Ang-II) (۲.۸ mg/kg/day) for ۴ weeks. DMSO or FABP۴ inhibitor BMS۳۰۹۴۰۳ (۵۰ mg/kg/day) was intraperitoneally injected for ۴ weeks. Ang II-infused mice, FABP۴ inhibitor (BMS۳۰۹۴۰۳) injected mice, and ventricular tissue were used for morphological studies, and histological and biochemical analyses (FABP۴ protein composition and expression).Results: Ang II infusion increased FABP۴ mRNA and protein expression in the mouse ventricular tissue. After treatment with FABP۴ inhibitor BMS۳۰۹۴۰۳ for ۴ weeks, mice showed improved cardiac structure and function as detected by echocardiography. BMS۳۰۹۴۰۳ suppressed cardiac and systemic inflammatory response, reduced collagen deposition, and mRNA expression of collagen type I (COL۱A۱) and collagen type III (COL۳A۱) in Ang II-infused mice. BMS۳۰۹۴۰۳ also reduced the number of α-smooth muscle actin (α-SMA)+cells and decreased the mRNA expression of α-SMA, matrix metalloproteinases-۲ (MMP-۲), MMP-۹, and transforming growth factor-β (TGF‑β) in ventricular tissue.Conclusion: The inhibitory effect of BMS۳۰۹۴۰۳ on cardiac fibrosis might be associated with inhibition of NLRP۳ inflammasome activation, which Ang II activated. Thus, our data speculated that inhibition of FABP۴ could significantly induce cardiac fibrosis.

Keywords:

Cardiac fibrosis , Collagen , FABP۴ , Fibroblast , NLRP۳