CHOP Increases TRIB3-Dependent miR-208 Expression to Potentiate Vascular Smooth Muscle Cell Proliferation and Migration by Downregulating TIMP3 in Atherosclerosis.

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.