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 < 0.05), a lower intimal media ratio (p < 0.02), and a tendency to higher lumen area, compared to PCSK9+/+ mice. When compared with PCSK9-/-, lesions of PCSK9+/+ mice had a higher content of SMCs (p < 0.05) and collagen (p < 0.05), while no difference was observed in the accumulation of macrophages. PCSK9 was detectable in both left and right carotids artery in regions occupied by medial and neointimal SMCs. SMCs freshly isolated from PCSK9-/-, when compared to PCSK9+/+ cells, showed higher levels of α-smooth muscle actin (α-SMA; 2.24 ± 0.36 fold; p < 0.01) and myosin heavy chain II (MHC-II; 8.65 ± 1.55 fold; p < 0.01), and lower levels of caldesmon mRNA(-54 ± 14%; p < 0.01). 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 < 0.01), MHC-II (-45% ± 25.5 fold: p = 0.06) and calponin (-25% ± 0.8 fold: p < 0.05) and induction of caldesmon mRNA (1.46 ± 0.3 fold; p < 0.05). Proliferation rate of SMCs 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.
PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement / N. Ferri, S. Marchianò, G. Tibolla, R. Baetta, A. Dhyani, M. Ruscica, P. Uboldi, A.L. Catapano, A. Corsini. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 253(2016 Oct), pp. 214-224.
|Titolo:||PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement|
MARCHIANO', SILVIA (Secondo)
CATAPANO, ALBERICO LUIGI (Penultimo)
CORSINI, ALBERTO (Ultimo)
|Parole Chiave:||PCSK9; Smooth muscle cells; Restenosis; Small G proteins; Cell proliferation; Cell migration|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore MED/04 - Patologia Generale
|Data di pubblicazione:||ott-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.910|
|Appare nelle tipologie:||01 - Articolo su periodico|