Limits...
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 vascular endothelial capillary assembly in vitro.(A) HUVECs were treated with DMSO or gradient concentrations (0.2μM -10μM) of lonafarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (B) HUVECs were plated onto matrigel and treated with DMSO or different concentrations (0.2μM -10μM) of lonafarnib. Photographs were taken 6 hours later. (C) Experiments were performed as in (B), and the cumulative capillary length was calculated. Results are means ±SEM from three independent experiments; ***P < 0.001 versus Control, *P < 0.05 versus Control.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4390146&req=5

pone.0122830.g001: The effect of lonafarnib on vascular endothelial capillary assembly in vitro.(A) HUVECs were treated with DMSO or gradient concentrations (0.2μM -10μM) of lonafarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (B) HUVECs were plated onto matrigel and treated with DMSO or different concentrations (0.2μM -10μM) of lonafarnib. Photographs were taken 6 hours later. (C) Experiments were performed as in (B), and the cumulative capillary length was calculated. Results are means ±SEM from three independent experiments; ***P < 0.001 versus Control, *P < 0.05 versus Control.

Mentions: To investigate the potential effect of lonafarnib on neovascularization in vitro, we treated HUVECs with gradient concentrations of lonafarnib and performed matrigel-based capillary assembly assay. The farnesylation of HDJ-2, one of the major substrates of farnesyl transferase, was used as a read-out for the enzyme inhibition. As shown in Fig 1A, lonafarnib inhibited HDJ-2 farnesylation in a dose-dependent manner, as demonstrated by the increase of the non-farnesylated HDJ-2 (upper band) and concomitant decrease of the farnesylated HDJ-2 (lower band). We then plated HUVECs onto matrigel and examined the effect of lonafarnib on the capillary-like structures 6 hours later. As shown in Fig 1B, lonafarnib-treated cells displayed remarkable defects in capillary assembly as compared to the control group. By measuring the cumulative capillary length, we found that lonafarnib treatment (0.2 μM -10 μM) led to a significant dose-dependent decrease in capillary assembly (Fig 1C). Thus, the data showed that lonafarnib impairs neovascularization by directly targeting the 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 vascular endothelial capillary assembly in vitro.(A) HUVECs were treated with DMSO or gradient concentrations (0.2μM -10μM) of lonafarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (B) HUVECs were plated onto matrigel and treated with DMSO or different concentrations (0.2μM -10μM) of lonafarnib. Photographs were taken 6 hours later. (C) Experiments were performed as in (B), and the cumulative capillary length was calculated. Results are means ±SEM from three independent experiments; ***P < 0.001 versus Control, *P < 0.05 versus Control.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122830.g001: The effect of lonafarnib on vascular endothelial capillary assembly in vitro.(A) HUVECs were treated with DMSO or gradient concentrations (0.2μM -10μM) of lonafarnib for 24 hours, and HDJ-2 farnesylation was analyzed by Western blot. (B) HUVECs were plated onto matrigel and treated with DMSO or different concentrations (0.2μM -10μM) of lonafarnib. Photographs were taken 6 hours later. (C) Experiments were performed as in (B), and the cumulative capillary length was calculated. Results are means ±SEM from three independent experiments; ***P < 0.001 versus Control, *P < 0.05 versus Control.
Mentions: To investigate the potential effect of lonafarnib on neovascularization in vitro, we treated HUVECs with gradient concentrations of lonafarnib and performed matrigel-based capillary assembly assay. The farnesylation of HDJ-2, one of the major substrates of farnesyl transferase, was used as a read-out for the enzyme inhibition. As shown in Fig 1A, lonafarnib inhibited HDJ-2 farnesylation in a dose-dependent manner, as demonstrated by the increase of the non-farnesylated HDJ-2 (upper band) and concomitant decrease of the farnesylated HDJ-2 (lower band). We then plated HUVECs onto matrigel and examined the effect of lonafarnib on the capillary-like structures 6 hours later. As shown in Fig 1B, lonafarnib-treated cells displayed remarkable defects in capillary assembly as compared to the control group. By measuring the cumulative capillary length, we found that lonafarnib treatment (0.2 μM -10 μM) led to a significant dose-dependent decrease in capillary assembly (Fig 1C). Thus, the data showed that lonafarnib impairs neovascularization by directly targeting the 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