Abstract
Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.
Highlights
Hypertension is a major risk factor for the development of cardiovascular diseases (CVDs)
Yes-associated protein and TAZ are major downstream effectors of the Hippo pathway, phosphorylated YAP (p-YAP) and phosphorylated TAZ (p-TAZ) are an inactive form and retained in the cytosolic apartment, and YAP/TAZ activation is initiated by dephosphorylation and promoted the relocation into the nucleus from the cytosolic apartment (Totaro et al, 2018)
Immunofluorescence staining showed that the total immunofluorescence intensity of YAP and its colocalization with the nucleus were significantly increased in the aorta of AngII mice, which was reduced in verteporfintreated hypertensive mice (Figures 1E,F)
Summary
Hypertension is a major risk factor for the development of cardiovascular diseases (CVDs). Long-term high blood pressure causes vascular injury, which is associated with endothelial dysfunction and increased arterial stiffness and thickness (Ponticos and Smith, 2014). The mechanisms of hypertension-induced vascular injury are not fully understood. It is well-known that high blood pressure has hemodynamic derangement, such as increased hemodynamic stress and blood flow turbulence. It has been shown that the Hippo/YAP pathway can be activated by sensing extracellular stiffness and play an important role in the regulation of cell proliferation, apoptosis, and differentiation (Moya and Halder, 2019; Rausch and Hansen, 2020). The activation of YAP/TAZ promotes vascular inflammation and atherogenesis (Wang L. et al, 2016; Ranchoux et al, 2018; Wang and Zhang, 2020)
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