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Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway

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ABSTRACT

Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. The intracellular mediator and external anti-inflammatory external signal in the vascular wall have been reported to protect endothelial cells, in part due to nitric oxide (NO) production. This study was designed to examine whether NM exhibit endothelium dependent vascular relaxation through Akt/endothelial nitric oxide synthase (eNOS) activation and generation of NO. NM enhanced Akt/eNOS phosphorylation and NO production in a dose- and time-dependent manner in human umbilical vein endothelial cells (HUVECs) and aorta tissues obtained from rats treated with various concentrations of NM. NM concomitantly decreased arginase activity, which could increase the available arginine substrate for NO production. Moreover, we investigated whether NM increased NO bioavailability and decreased aortic relaxation response to an eNOS inhibitor in the aorta. These results suggest that NM increases NO generation via the Akt/eNOS signaling pathway, leading to endothelium-dependent vascular relaxation. Therefore, the vasorelaxing action of NM may contribute to the regulation of cardiovascular function.

No MeSH data available.


Nafamostat mesilate (NM) stimulates the production of nitric oxide and inhibits arginase activity in human umbilical vein endothelial cells (HUVECs).(A) NO production in HUVECs treated with various concentrations (10~1000 ng/ml) of NM for 2 h. (B) Arginase activity measured in HUVECs treated with various concentrations (30~1000 ng/mL) of NM for 2 h. Bars represent means±standard error (n=3).
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Figure 2: Nafamostat mesilate (NM) stimulates the production of nitric oxide and inhibits arginase activity in human umbilical vein endothelial cells (HUVECs).(A) NO production in HUVECs treated with various concentrations (10~1000 ng/ml) of NM for 2 h. (B) Arginase activity measured in HUVECs treated with various concentrations (30~1000 ng/mL) of NM for 2 h. Bars represent means±standard error (n=3).

Mentions: NO is an endothelium derived relaxing factor, which plays an important role in the control of vascular tone and function. Phosphorylation of eNOS and Akt leads to stimulation of NO production in endothelial cells. We therefore measured the level of NO produced by HUVECs treated with different doses of NM. Fig. 2A shows that NM treatment dose-dependently increased the production of NO in HUVECs.


Nafamostat mesilate promotes endothelium-dependent vasorelaxation via the Akt-eNOS dependent pathway
Nafamostat mesilate (NM) stimulates the production of nitric oxide and inhibits arginase activity in human umbilical vein endothelial cells (HUVECs).(A) NO production in HUVECs treated with various concentrations (10~1000 ng/ml) of NM for 2 h. (B) Arginase activity measured in HUVECs treated with various concentrations (30~1000 ng/mL) of NM for 2 h. Bars represent means±standard error (n=3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015001&req=5

Figure 2: Nafamostat mesilate (NM) stimulates the production of nitric oxide and inhibits arginase activity in human umbilical vein endothelial cells (HUVECs).(A) NO production in HUVECs treated with various concentrations (10~1000 ng/ml) of NM for 2 h. (B) Arginase activity measured in HUVECs treated with various concentrations (30~1000 ng/mL) of NM for 2 h. Bars represent means±standard error (n=3).
Mentions: NO is an endothelium derived relaxing factor, which plays an important role in the control of vascular tone and function. Phosphorylation of eNOS and Akt leads to stimulation of NO production in endothelial cells. We therefore measured the level of NO produced by HUVECs treated with different doses of NM. Fig. 2A shows that NM treatment dose-dependently increased the production of NO in HUVECs.

View Article: PubMed Central - PubMed

ABSTRACT

Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has anticoagulant and anti-inflammatory properties. The intracellular mediator and external anti-inflammatory external signal in the vascular wall have been reported to protect endothelial cells, in part due to nitric oxide (NO) production. This study was designed to examine whether NM exhibit endothelium dependent vascular relaxation through Akt/endothelial nitric oxide synthase (eNOS) activation and generation of NO. NM enhanced Akt/eNOS phosphorylation and NO production in a dose- and time-dependent manner in human umbilical vein endothelial cells (HUVECs) and aorta tissues obtained from rats treated with various concentrations of NM. NM concomitantly decreased arginase activity, which could increase the available arginine substrate for NO production. Moreover, we investigated whether NM increased NO bioavailability and decreased aortic relaxation response to an eNOS inhibitor in the aorta. These results suggest that NM increases NO generation via the Akt/eNOS signaling pathway, leading to endothelium-dependent vascular relaxation. Therefore, the vasorelaxing action of NM may contribute to the regulation of cardiovascular function.

No MeSH data available.