PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

Abstract Background and aims Proprotein convertase subtilisin kexin type 9 (PCSK9) induces degradation of the low-density lipoprotein-receptor (LDLR). Smooth muscle cells (SMCs) in human atherosclerotic plaques and cultured SMCs express PCSK9. The present study aimed at defining the role of PCSK9 on vascular response to injury. Methods Carotid neointimal lesions were induced by positioning a non-occlusive collar in PCSK9 knock-out ( PCSK9 −/− ) and wild type littermate ( PCSK9 +/+ ) mice. Results In PCSK9 −/− mice, we observed a significantly less intimal thickening ( p p PCSK9 +/+ mice. When compared with PCSK9 −/− , lesions of PCSK9 +/+ mice had a higher content of SMCs ( p p PCSK9 −/− , when compared to PCSK9 +/+ cells, showed higher levels of α-smooth muscle actin ( α-SMA ; 2.24 ± 0.36 fold; p MHC-II ; 8.65 ± 1.55 fold; p caldesmon mRNA(−54 ± 14%; p PCSK9 −/− cells also showed a slower proliferation rate, and an impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9 −/− SMCs, led to a downregulation of α-SMA (−56 ± 2%; p MHC-II (−45% ± 25.5 fold: p  = 0.06) and calponin (−25% ± 0.8 fold: p caldesmon mRNA (1.46 ± 0.3 fold; p PCSK9 −/− was significantly lower compared to PCSK9 reconstituted cells. Conclusions Taken together, the present results suggest that PCSK9, by sustaining SMC synthetic phenotype, proliferation, and migration, may play a pro-atherogenic role in the arterial wall.