akb-9778 and Disease-Models--Animal

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.. 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.. 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.

Topics: Aniline Compounds; Animals; Antihypertensive Agents; Blood Pressure; Cells, Cultured; Diabetes Mellitus; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypertension; Mice, Inbred C57BL; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Signal Transduction; Sulfonic Acids; Treatment Outcome; United States

Administration of interleukin (IL)-2 has led to a durable response in patients with advanced renal cancer and melanoma but is restricted for clinical application because of adverse effects, including the vascular leak syndrome (VLS). VLS is associated with increased circulating levels of the Tie2 antagonist ligand, angiopoietin 2, and decreased Tie2 receptor phosphorylation and downstream signaling in endothelial cells (ECs). Given that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a specific membrane phosphatase in ECs that dephosphorylates Tie2, the effects of targeting VE-PTP by a selective inhibitor AKB-9778 (AKB) in terms of VLS and antitumor efficacy were examined in this study. The authors found, by targeting VE-PTP, that the antitumor effects induced by IL-2 were augmented [tumor-free 44% (IL-2 alone) vs. 87.5% (IL-2+AKB)], associated with enhanced immune cell infiltrate (90% increase for CD8 T cells and natural killer cells). In addition, the side effects of IL-2 therapy were lessened, as demonstrated by diminished lung weight (less vascular leakage) as well as reduced cytokine levels (serum HMGB1 from 137.04±2.69 to 43.86±3.65 pg/mL; interferon-γ from 590.52±90.52 to 31.37±1.14 pg/mL). The authors further sought to determine the potential mechanism of the action of AKB-9778. The findings suggest that AKB-9778 may function through reducing serum angiopoietin 2 level and regulating EC viability. These findings provide insights into the targeting VE-PTP to improve tolerance and efficacy of IL-2 therapy and highlight the clinical potential of AKB-9778 for treating patients with VLS and cancer.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Disease Models, Animal; Drug Synergism; Female; Gene Expression; Genes, Reporter; Humans; Inflammation Mediators; Interleukin-2; Liver Neoplasms; Mice; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Sulfonic Acids; Xenograft Model Antitumor Assays