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.