Abstract
Background and AimsThe YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.MethodsThe effect of high glucose on YAP/TAZ signaling was firstly evaluated in vitro on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in vivo in db/db mice.ResultsIn vitro, we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased.ConclusionWith the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells in vitro and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.
Highlights
High glucose-induced endothelial dysfunction is a crucial initiating factor in the development of diabetes-associated vascular complications which, in turn, are responsible for shortened life expectancy, high rate of hospitalization, and high morbidity and mortality in patients with diabetes (Grundy et al, 2002; Schalkwijk and Stehouwer, 2005; Beckman and Creager, 2016).The diabetic endothelium is characterized by increased expression of adhesion molecules and proinflammatory cytokines, resulting in a prothrombotic and proinflammatory state that favors the development of atherosclerosis (Anderson et al, 1995; Plutzky, 2003)
With the current study we investigated the importance of YAP/TAZ signaling on endothelial cell activation and vascular inflammation in the settings of diabetes
Using in vitro and in vivo approaches, we demonstrated that YAP signaling is activated in the diabetic vasculature and plays a role in the regulation of endothelial inflammation and monocyte attachment induced by high glucose
Summary
High glucose-induced endothelial dysfunction is a crucial initiating factor in the development of diabetes-associated vascular complications which, in turn, are responsible for shortened life expectancy, high rate of hospitalization, and high morbidity and mortality in patients with diabetes (Grundy et al, 2002; Schalkwijk and Stehouwer, 2005; Beckman and Creager, 2016).The diabetic endothelium is characterized by increased expression of adhesion molecules and proinflammatory cytokines, resulting in a prothrombotic and proinflammatory state that favors the development of atherosclerosis (Anderson et al, 1995; Plutzky, 2003). YAP and TAZ are transcriptional regulators and the main downstream mediators of the Hippo pathway, which regulates cell proliferation, survival and differentiation, controlling organ development and tissue regeneration (Pan, 2010; Yu and Guan, 2013; Piccolo et al, 2014). Inhibition of the Hippo pathway promotes YAP and TAZ dephosphorylation and activation, followed by their translocation into the nucleus where they interact with the transcriptional enhancer associated domain (TEAD) leading to the activation of target genes associated with cell proliferation and differentiation (Piccolo et al, 2014). The YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Whether YAP/TAZ signaling is implicated in diabetes-associated vascular complications is not known
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