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.
BACKGROUND AND AIMS: Proprotein convertase subtilisin kexin type 9 (PCSK9) induces degradation of the low-density lipoprotein-receptor (LDLR). Smooth muscle cells (SMCs) in humanatherosclerotic 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.
Authors: José Tuñón; Lina Badimón; Marie-Luce Bochaton-Piallat; Bertrand Cariou; Mat J Daemen; Jesus Egido; Paul C Evans; Imo E Hoefer; Daniel F J Ketelhuth; Esther Lutgens; Christian M Matter; Claudia Monaco; Sabine Steffens; Erik Stroes; Cécile Vindis; Christian Weber; Magnus Bäck Journal: Cardiovasc Res Date: 2019-01-01 Impact factor: 10.787
Authors: Angelos D Karagiannis; Martin Liu; Peter P Toth; Shijia Zhao; Devendra K Agrawal; Peter Libby; Yiannis S Chatzizisis Journal: Curr Atheroscler Rep Date: 2018-03-10 Impact factor: 5.113
Authors: Gopala K Yakala; Hector A Cabrera-Fuentes; Gustavo E Crespo-Avilan; Chutima Rattanasopa; Alexandrina Burlacu; Benjamin L George; Kaviya Anand; David Castaño Mayan; Maria Corlianò; Sauri Hernández-Reséndiz; Zihao Wu; Anne M K Schwerk; Amberlyn L J Tan; Laia Trigueros-Motos; Raphael Chèvre; Tricia Chua; Robert Kleemann; Elisa A Liehn; Derek J Hausenloy; Sujoy Ghosh; Roshni R Singaraja Journal: Arterioscler Thromb Vasc Biol Date: 2019-03 Impact factor: 8.311