title: Lonafarnib is a potential inhibitor for neovascularization.
abstract: Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.
authors: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors: Linlin
authors: L
authors: Sun
authors: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Songbo
authors: S
authors: Xie
authors: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Guoyuan
authors: G
authors: Peng
authors: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Jian
authors: J
authors: Wang
authors: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Yuanyuan
authors: Y
authors: Li
authors: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors: Juan
authors: J
authors: Qin
authors: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China.
authors: Diansheng
authors: D
authors: Zhong
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D001057:Apolipoproteins E; D003598:Cytoskeletal Proteins; D010880:Piperidines; D011725:Pyridines; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes