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Published on: October 15, 2010
VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes
Mauro Siragusa1,2, Alberto Fernando Oliveira Justo1, Pedro Felipe Malacarne3
1Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Aims:
Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates Tie-2 as well as CD31, VE-cadherin, and vascular endothelial growth factor receptor 2 (VEGFR2). The latter form a signal transduction complex that mediates the endothelial cell response to shear stress, including the activation of the endothelial nitric oxide (NO) synthase (eNOS). As VE-PTP expression is increased in diabetes, we investigated the consequences of VE-PTP inhibition (using AKB-9778) on blood pressure in diabetic patients and the role of VE-PTP in the regulation of eNOS activity and vascular reactivity.
Methods And Results:
In diabetic patients AKB-9778 significantly lowered systolic and diastolic blood pressure. This could be linked to elevated NO production, as AKB increased NO generation by cultured endothelial cells and elicited the NOS inhibitor-sensitive relaxation of endothelium-intact rings of mouse aorta. At the molecular level, VE-PTP inhibition increased the phosphorylation of eNOS on Tyr81 and Ser1177 (human sequence). The PIEZO1 activator Yoda1, which was used to mimic the response to shear stress, also increased eNOS Tyr81 phosphorylation, an effect that was enhanced by VE-PTP inhibition. Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. Finally, phosphorylation of eNOS on Tyr80 (murine sequence) was found to be reduced in diabetic mice and diabetes-induced endothelial dysfunction (isolated aortic rings) was blunted by VE-PTP inhibition.
Conclusions:
VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE-cadherin/VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81. VE-PTP inhibition, therefore, represents an attractive novel therapeutic option for diabetes-induced endothelial dysfunction and hypertension.
Insights
Vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibition lowers blood pressure in diabetic patients by enhancing nitric oxide (NO) production and improving endothelial function. This approach offers a promising new therapy for diabetes-induced hypertension and vascular dysfunction.
Area of Science:
- Cardiovascular Research
- Endothelial Cell Biology
- Pharmacology
Background:
- Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates key proteins in endothelial cells, including Tie-2, CD31, VE-cadherin, and VEGFR2, which are critical for shear stress response and endothelial nitric oxide synthase (eNOS) activation.
- VE-PTP expression is elevated in diabetes, contributing to endothelial dysfunction and hypertension.
Purpose of the Study:
- To investigate the effects of VE-PTP inhibition using AKB-9778 on blood pressure in diabetic patients.
- To elucidate the role of VE-PTP in regulating eNOS activity and vascular reactivity in the context of diabetes.
Main Methods:
- Administered AKB-9778 to diabetic patients and assessed blood pressure changes.
- Evaluated NO generation in cultured endothelial cells and vascular relaxation in mouse aortic rings.
- Investigated molecular mechanisms of eNOS regulation, including phosphorylation and kinase activity, in response to VE-PTP inhibition and shear stress mimicry (Yoda1).
- Examined VE-PTP interaction with eNOS and its dephosphorylation activity in vitro.
- Assessed eNOS phosphorylation and endothelial function in diabetic mouse models.
Main Results:
- AKB-9778 significantly reduced systolic and diastolic blood pressure in diabetic patients.
- VE-PTP inhibition increased NO production in endothelial cells and induced NOS inhibitor-sensitive relaxation in aortic rings.
- VE-PTP inhibition enhanced eNOS phosphorylation at Tyr81 and Ser1177, an effect amplified by Yoda1.
- Abelson-tyrosine protein kinase (ABL)1 and Src were identified as key kinases for eNOS Tyr81 phosphorylation.
- VE-PTP directly dephosphorylated eNOS Tyr81 in vitro and formed a complex with eNOS.
- Phosphorylation of eNOS Tyr80 was reduced in diabetic mice, and VE-PTP inhibition ameliorated diabetes-induced endothelial dysfunction.
Conclusions:
- VE-PTP inhibition improves endothelial function and lowers blood pressure by enhancing eNOS activity.
- This occurs through both indirect activation of the Tie-2 and CD31/VE-cadherin/VEGFR2 complex, and direct dephosphorylation of eNOS Tyr81.
- VE-PTP inhibition represents a promising therapeutic strategy for managing diabetes-induced endothelial dysfunction and hypertension.
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