Yanan Guo1,2, Zhihan Tang1,3, Binjie Yan1,3, Hao Yin1,4, Shi Tai2, Juan Peng3, Yuting Cui1,3, Yu Gui1, Darrell Belke1, Shenghua Zhou2, Xi-Long Zheng1. 1. Departments of Biochemistry and Molecular Biology and Physiology and Pharmacology (Y. Guo, Z.T., B.Y., H.Y., Y. Gui, X.-L. Zheng). 2. Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (Y. Guo, S.T., S.Z.). 3. Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan (Z.T., B.Y., J.P., Y.C.). 4. Now with Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada (H.Y.).
Abstract
OBJECTIVE: PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin. CONCLUSIONS: Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.
OBJECTIVE: PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin. CONCLUSIONS: Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.
Authors: Arianna Toscano; Maria Cinquegrani; Michele Scuruchi; Antonino Di Pino; Salvatore Piro; Viviana Ferrara; Carmela Morace; Alberto Lo Gullo; Egidio Imbalzano; Francesco Purrello; Giovanni Squadrito; Roberto Scicali; Giuseppe Mandraffino Journal: Biomolecules Date: 2022-04-09
Authors: Roberto Scicali; Giuseppe Mandraffino; Michele Scuruchi; Alberto Lo Gullo; Antonino Di Pino; Viviana Ferrara; Carmela Morace; Caterina Oriana Aragona; Giovanni Squadrito; Francesco Purrello; Salvatore Piro Journal: Biomedicines Date: 2022-07-15