Activation of Yes-Associated Protein/PDZ-Binding Motif Pathway Contributes to Endothelial Dysfunction and Vascular Inflammation in AngiotensinII Hypertension

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.

The regulation of yes-associated protein/transcriptional coactivator with PDZ-binding motif and their roles in vascular endothelium

“…Atherosclerosis is the main inducer of cardiovascular diseases. Studies have confirmed that the activation of YAP/TAZ in endothelial cells plays an important role in the occurrence and development of atherosclerosis by promoting an inflammatory response (12,67,73,74). Overexpression of YAP in an ApoE −/− mouse model upregulated the inflammatory related factors in arterial endothelial cells, such as IL-6, VCAM-1 and IL-8, and thus increased the atherosclerotic plaque and lesion range in aortic arch (8,33).…”

“…However, how the abovementioned factors regulate YAP/TAZ and whether there are other downstream target genes modulated by YAP/TAZ are not well clarified. Accumulating evidence has indicated that YAP/TAZ play a central role in modulating biological functions of the vascular endothelium, including inflammation, oxidative stress, and angiogenesis (12,67,(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87). Whether there are other biological functions of the vascular endothelium affected by YAP/TAZ are also worthy to be further studied.…”

Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases

“…The knocking down of the YAP/TAZ can also significantly reduce the expression of VCAM1 induced by TNF-α [ 53 ], which suggests that the endothelial YAP/TAZ may assist a vascular repair by regulating the inflammatory reaction. The dephosphorylation/activation of the endothelial YAP/TAZ signal in a high glucose microenvironment is considered as the key link [ 54 ]; this will increase the endothelial inflammation and monocyte attachment [ 53 , 55 ].…”

The Hippo-YAP pathway in various cardiovascular diseases: Focusing on the inflammatory response

“…Moreover, YAP aggravates the inflammatory response in the vascular endothelium under high glucose conditions. Similarly, in the aortas of Angiotensin II -induced hypertensive mice, treatment with the YAP/TAZ inhibitor v e r t e p o r fi n r e d u c e s m a c r o p h a g e i n fi l t r a t i o n a n d proinflammatory cytokine production (164). However, another study demonstrated that Tie2-mediated endothelial-specific knockout of Yap in mice resulted in mild endothelial inflammation and impaired microvessel permeability in lung, as evidenced by increased numbers of total cells, neutrophils, and macrophages and an increased neutrophil/macrophage ratio after LPS administration.…”