Knockdown of CHI3L1 Attenuates Venous Intimal Hyperplasia by Modulating Vascular Inflammation and Oxidative Stress via the JNK/ERK Pathway

Abstract

Background: Venous intimal hyperplasia (VIH) is the key pathological basis for early failure of arteriovenous fistula (AVF) and for stenosis of hemodialysis access. Chitinase-3-like protein 1 (CHI3L1) is highly expressed during cardiovascular remodeling and inflammation, but its role and underlying mechanisms in AVF-related VIH remain unclear.Methods: A rat AVF model was established, and VIH, inflammatory cell infiltration, and changes in the CHI3L1/c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) pathway were assessed at 7 and 21 days after surgery. Adenovirus-mediated CHI3L1 knockdown was used to evaluate its effects on VIH, oxidative stress, and inflammation. In vitro, a human vascular smooth muscle cell (VSMC) activation model was induced by platelet-derived growth factor-BB (PDGF-BB), and a stable CHI3L1-knockdown cell line was generated. VSMC proliferation, migration, phenotypic switch, oxidative stress, and inflammatory levels were evaluated, and the involvement of JNK/ERK signaling was investigated using the JNK agonist anisomycin.Results: In vivo, venous fistula tissue from the AVF model exhibited a significant increase in CHI3L1 expression, along with neointimal hyperplasia (NIH) and the presence of CD68+ macrophage infiltration (p < 0.001). CHI3L1 knockdown reduced JNK/ERK activation, attenuated neointimal thickening, macrophage infiltration, oxidative stress, and inflammatory responses, alongside a reversal in the downregulation of contractile marker proteins (p < 0.001). In vitro, PDGF-BB induced upregulation of CHI3L1 in VSMCs (p < 0.001). CHI3L1 knockdown suppressed VSMC proliferation, migration and the contractile-to-synthetic phenotypic switch, reduced inflammatory cytokine secretion and oxidative stress markers, and inhibited JNK/ERK phosphorylation (p < 0.001); these effects were partially reversed by anisomycin.Conclusion: CHI3L1 knockdown significantly inhibits activation of the JNK/ERK signaling pathway, mitigates vascular wall inflammation and oxidative stress, thereby blocking pathological phenotypic transformation, excessive proliferation, and migration of VSMCs, ultimately attenuating AVF-related VIH.