Archives of biochemistry and biophysics · 2025
HSPB1 suppresses oxLDL-induced vascular smooth muscle cell ferroptosis by inhibiting DPP4.
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Li Yi, Zhang Lijun, Zhang Qi, Zhang Yuke, Pan Shuang, Zhao Huanhuan, Zhang Lijun
Аннотация
BACKGROUND: Atherosclerosis is the major pathological basis of cardiovascular diseases. Vascular smooth muscle cell (VSMC) dysfunction and death induced by oxidized low-density lipoprotein (oxLDL) play a key role in atherosclerosis. Ferroptosis is a novel iron-dependent lipid peroxidation regulated cell death, which is implicated in atherosclerosis. However, whether oxLDL induces VSMC ferroptosis and the specific mechanism is unclear.
METHODS: To determine the effects of oxLDL on VSMC ferroptosis, LDH activity, MDA and Fe2+ content, glutathione peroxidase 4 (GPX4) expression and GPX enzyme activity were assayed. The level of lipid peroxidation was detected by C11 BODIPY fluorescence staining. RT-qPCR and Western blot were used to detect the mRNA and protein expressions of heat shock protein B1 (HSPB1), dipeptidyl peptidase 4 (DPP4) and nuclear factor kappa-B (NF-κB). The siRNAs, plasmids and Val-boropro were utilized to explore the roles of HSPB1/NF-κB/DPP4 in oxLDL-induced VSMC ferroptosis.
RESULTS: oxLDL increased LDH activity, Fe2+ content, lipid peroxidation and MDA content in VSMCs, which were inhibited by ferroptosis inhibitors Lip-1 and DFO. Moreover, oxLDL reduced GPX4 protein expression and GPX enzyme activity, indicating that oxLDL induces VSMC ferroptosis. Notably, HSPB1 inhibited oxLDL-induced VSMC ferroptosis by reducing the accumulation of Fe2+ and lipid peroxidation and increasing GPX4 expression and activity. In addition, HSPB1 suppressed oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB. Furthermore, Val-boropro could rescue oxLDL-induced ferroptosis in VSMCs with HSPB1 knockdown by inhibiting DPP4.
CONCLUSIONS: This study reveals for the first time that HSPB1 suppresses oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB, providing new strategies for the prevention and treatment of atherosclerosis.
METHODS: To determine the effects of oxLDL on VSMC ferroptosis, LDH activity, MDA and Fe2+ content, glutathione peroxidase 4 (GPX4) expression and GPX enzyme activity were assayed. The level of lipid peroxidation was detected by C11 BODIPY fluorescence staining. RT-qPCR and Western blot were used to detect the mRNA and protein expressions of heat shock protein B1 (HSPB1), dipeptidyl peptidase 4 (DPP4) and nuclear factor kappa-B (NF-κB). The siRNAs, plasmids and Val-boropro were utilized to explore the roles of HSPB1/NF-κB/DPP4 in oxLDL-induced VSMC ferroptosis.
RESULTS: oxLDL increased LDH activity, Fe2+ content, lipid peroxidation and MDA content in VSMCs, which were inhibited by ferroptosis inhibitors Lip-1 and DFO. Moreover, oxLDL reduced GPX4 protein expression and GPX enzyme activity, indicating that oxLDL induces VSMC ferroptosis. Notably, HSPB1 inhibited oxLDL-induced VSMC ferroptosis by reducing the accumulation of Fe2+ and lipid peroxidation and increasing GPX4 expression and activity. In addition, HSPB1 suppressed oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB. Furthermore, Val-boropro could rescue oxLDL-induced ferroptosis in VSMCs with HSPB1 knockdown by inhibiting DPP4.
CONCLUSIONS: This study reveals for the first time that HSPB1 suppresses oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB, providing new strategies for the prevention and treatment of atherosclerosis.