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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 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.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.

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 centrosome reorientation in vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or 10 μM lonafarnib for 8 hours. Cells were then fixed and stained with anti-α-tubulin antibody, anti-γ-tubulin antibody and DAPI to visualize microtubules(green), centrosomes (red) and nuclei (blue), respectively. (B) Experiments were performed as in (A), and the percentage of polarized cells with proper centrosome reorientation at the wound margin was quantified. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.
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pone.0122830.g004: The effect of lonafarnib on centrosome reorientation in vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or 10 μM lonafarnib for 8 hours. Cells were then fixed and stained with anti-α-tubulin antibody, anti-γ-tubulin antibody and DAPI to visualize microtubules(green), centrosomes (red) and nuclei (blue), respectively. (B) Experiments were performed as in (A), and the percentage of polarized cells with proper centrosome reorientation at the wound margin was quantified. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.

Mentions: To gain more mechanistic insight into the inhibition of neovascularization by lonafarnib, we evaluated the effect of lonafarnib on the reorientation of the centrosome towards the leading edge of cells, which is a key step for endothelial cell motility[10]. HUVECs were scratched and treated with 10 μM lonafarnib for 8 hours. Cells were then fixed and immunostained to visualize microtubules, centrosomes and nuclei., As shown in the representative image in Fig 4A and quantified in Fig 4B, in the control group, cells at the wound margin exhibited a typical polarized morphology with centrosomes localized between the nuclei and the leading edge. In contrast, lonafarnib-treated cells displayed significant defects in the position of centrosomes, which randomly localized and failed to properly orient themselves to the direction of motility. Thus, the data showed that lonafarnib significantly disturbs the reorientation of centrosome in the motile vascular endothelial cells.


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 centrosome reorientation in vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or 10 μM lonafarnib for 8 hours. Cells were then fixed and stained with anti-α-tubulin antibody, anti-γ-tubulin antibody and DAPI to visualize microtubules(green), centrosomes (red) and nuclei (blue), respectively. (B) Experiments were performed as in (A), and the percentage of polarized cells with proper centrosome reorientation at the wound margin was quantified. 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.g004: The effect of lonafarnib on centrosome reorientation in vascular endothelial cells.(A) HUVECs were scratched and treated with DMSO or 10 μM lonafarnib for 8 hours. Cells were then fixed and stained with anti-α-tubulin antibody, anti-γ-tubulin antibody and DAPI to visualize microtubules(green), centrosomes (red) and nuclei (blue), respectively. (B) Experiments were performed as in (A), and the percentage of polarized cells with proper centrosome reorientation at the wound margin was quantified. Results are means ±SEM from three independent experiments, ***P < 0.001 versus Control.
Mentions: To gain more mechanistic insight into the inhibition of neovascularization by lonafarnib, we evaluated the effect of lonafarnib on the reorientation of the centrosome towards the leading edge of cells, which is a key step for endothelial cell motility[10]. HUVECs were scratched and treated with 10 μM lonafarnib for 8 hours. Cells were then fixed and immunostained to visualize microtubules, centrosomes and nuclei., As shown in the representative image in Fig 4A and quantified in Fig 4B, in the control group, cells at the wound margin exhibited a typical polarized morphology with centrosomes localized between the nuclei and the leading edge. In contrast, lonafarnib-treated cells displayed significant defects in the position of centrosomes, which randomly localized and failed to properly orient themselves to the direction of motility. Thus, the data showed that lonafarnib significantly disturbs the reorientation of centrosome in the motile vascular endothelial cells.

Bottom Line: 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.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.

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