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Lonafarnib is a potential inhibitor for neovascularization.

Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.

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.

No MeSH data available.


Related in: MedlinePlus

The effect of lonafarnib on the motility of vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or different concentrations (0.2μM -20μM) of lonafarnib, and wound margins were photographed 24 hours later. (B) Experiments were performed as in (A), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control; **P < 0.01 versus Control; *P < 0.05 versus Control. (C) HUVECs were treated with DMSO or 10μM tipifarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (D) HUVECs were scratched and treated with DMSO or 10μM tipifarnib, and wound margins were photographed 24 hours later. (E) Experiments were performed as in (D), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.
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pone.0122830.g002: The effect of lonafarnib on the motility of vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or different concentrations (0.2μM -20μM) of lonafarnib, and wound margins were photographed 24 hours later. (B) Experiments were performed as in (A), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control; **P < 0.01 versus Control; *P < 0.05 versus Control. (C) HUVECs were treated with DMSO or 10μM tipifarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (D) HUVECs were scratched and treated with DMSO or 10μM tipifarnib, and wound margins were photographed 24 hours later. (E) Experiments were performed as in (D), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.

Mentions: The motility and proliferation of the endothelial cells are essential for capillary assembly[9]. We then sought to examine the effect of lonafarnib on cell motility using the standard wound healing assay. As shown in Fig 2A, in the control group, a complete wound closure was observed 24 hours after scratching in HUVECs. In contrast, there was a significant impairment in wound closure in lonafarnib-treated cells. Lonafarnib treatment (0.2 μM -20 μM) led to a dose-dependent decrease in cell motility, as demonstrated by Fig 2B. To validate our results, we treat HUVECs with tipifarnib, another specific farnesyl transferase inhibitor, which remarkably decreased HDJ-2 farnesylation (Fig 2C). Similarly, we found that tipifarnib (10 μM) was able to suppress wound closure significantly (Fig 2D and 2E), confirming the inhibitory effect of this group of agents on cell motility.


Lonafarnib is a potential inhibitor for neovascularization.

Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D - PLoS ONE (2015)

The effect of lonafarnib on the motility of vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or different concentrations (0.2μM -20μM) of lonafarnib, and wound margins were photographed 24 hours later. (B) Experiments were performed as in (A), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control; **P < 0.01 versus Control; *P < 0.05 versus Control. (C) HUVECs were treated with DMSO or 10μM tipifarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (D) HUVECs were scratched and treated with DMSO or 10μM tipifarnib, and wound margins were photographed 24 hours later. (E) Experiments were performed as in (D), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390146&req=5

pone.0122830.g002: The effect of lonafarnib on the motility of vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or different concentrations (0.2μM -20μM) of lonafarnib, and wound margins were photographed 24 hours later. (B) Experiments were performed as in (A), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control; **P < 0.01 versus Control; *P < 0.05 versus Control. (C) HUVECs were treated with DMSO or 10μM tipifarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (D) HUVECs were scratched and treated with DMSO or 10μM tipifarnib, and wound margins were photographed 24 hours later. (E) Experiments were performed as in (D), and the extent of wound closure was quantified by measuring the wound area compared with the initial wound area. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.
Mentions: The motility and proliferation of the endothelial cells are essential for capillary assembly[9]. We then sought to examine the effect of lonafarnib on cell motility using the standard wound healing assay. As shown in Fig 2A, in the control group, a complete wound closure was observed 24 hours after scratching in HUVECs. In contrast, there was a significant impairment in wound closure in lonafarnib-treated cells. Lonafarnib treatment (0.2 μM -20 μM) led to a dose-dependent decrease in cell motility, as demonstrated by Fig 2B. To validate our results, we treat HUVECs with tipifarnib, another specific farnesyl transferase inhibitor, which remarkably decreased HDJ-2 farnesylation (Fig 2C). Similarly, we found that tipifarnib (10 μM) was able to suppress wound closure significantly (Fig 2D and 2E), confirming the inhibitory effect of this group of agents on cell motility.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.

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.

No MeSH data available.


Related in: MedlinePlus