FABP3 regulates vascular remodeling and endothelial-mesenchymal transition through NF-κB activation in aged mice fed a high-fat diet

BACKGROUND: Aging and obesity synergistically promote pathological vascular remodeling mediated by endothelial-mesenchymal transition (EndMT). Fatty acid-binding protein 3 (FABP3) maintains fatty acid homeostasis and cardiovascular function; however, its role in EndMT-driven vascular remodeling under combined aging and obesity remains unclear. This study aimed to elucidate the regulatory mechanism of FABP3 in aging- and obesity-associated vascular remodeling. METHODS: Young (6-week-old) and aged (18-month-old) C57BL/6J mice were fed normal chow or a 16-week high-fat diet (HFD). Carotid pathology, oxidative stress, inflammation, and EndMT were assessed via histological and immunostaining. Transcriptomic sequencing, qRT-PCR, and Western blotting were used to detect FABP3, NF-κB signaling, senescence, and EndMT markers. In vitro, palmitic acid (PA)-stimulated HUVECs with FABP3 knockdown, rhFABP3 rescue, or NF-κB inhibitor treatment were used for mechanistic validation. RESULTS: HFD induced body weight gain, increased epididymal fat mass, and elevated serum lipids, with more severe metabolic disorders in aged mice. Aging aggravated carotid intima-media thickening, fibrosis, lipid deposition, oxidative stress, and inflammatory infiltration; these abnormalities were further exacerbated by HFD. EndMT was activated in aged vasculature, with reduced endothelial markers (CD31, VE-cadherin) and elevated mesenchymal markers (α-SMA, TGF-β, COL1A1, N-cadherin). FABP3 and core NF-κB signaling components (NF-κB, p-NF-κB, IκBα, p-IκBα) were significantly upregulated in HFD-fed aged mouse carotids, paralleling EndMT severity. PA triggered HUVEC senescence and EndMT. FABP3 silencing or NF-κB inhibition alleviated these phenotypes, whereas rhFABP3 supplementation reversed the protective effects of FABP3 knockdown. CONCLUSION: This study demonstrated that FABP3 overexpression activates NF-κB signaling, aggravating endothelial inflammation, promoting abnormal EndMT, and accelerating vascular remodeling in aged obese mice. These findings provide novel mechanistic insights and potential therapeutic targets for aging- and obesity-related cardiovascular diseases.