Background: C/EBP homologous protein (CHOP) has been identified as a suitable therapeutic target to combat atherosclerosis but the mechanism has not been fully studied. Here, we sought to define the role and underlying mechanism of CHOP in atherosclerosis.
Methods: Mouse models of atherosclerosis in ApoE-/- mice were established by high-fat feeding, where miR-208 expression was determined. Then atherosclerotic plaque tissues were isolated from the model mice. Loss- and gain-function assays were performed on trypsinized vascular smooth muscle cells (VSMCs) to test the in vitro effect of CHOP in controlling the tribbles homologue 3 (TRIB3)/microRNA-208 (miR-208)/tissue inhibitor of metalloproteinases-3 (TIMP3) axis in atherosclerosis by determining cell proliferation and migration as well as blood lipid levels. Moreover, expression of α-smooth muscle actin (α-SMA) and type I collagen expression was determined using immunofluorescence staining to assess plaque stability in mice.
Results: miR-208 expression was elevated in atherosclerosis samples and miR-208 overexpression promoted proliferation and migration of VSMCs but diminished plaque stability in mice. TIMP3 was targeted by miR-208, which could be abrogated by upregulation of TIMP3. In addition, CHOP increased TRIB3 expression to upregulate miR-208 and to downregulate TIMP3, which potentiated VSMC proliferation and migration in vitro and in vivo.
Conclusion: Taken together, inhibition of CHOP may inhibit the proliferation and migration of VSMCs as well as reduce the levels of TC, TG, and LDL-C but increase the level of HDL-C through the TRIB3/miR-208/TIMP3 axis, thereby inhibiting the progression of atherosclerosis.
Keywords: Atherosclerosis; CHOP; MicroRNA-208; TIMP3; TRIB3; Vascular smooth muscle cells.
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