Palmitic acid dysregulates the Hippo-YAP pathway and inhibits angiogenesis by inducing mitochondrial damage and activating the cytosolic DNA sensor cGAS-STING-IRF3 signaling [Cell Biology]

Impaired angiogenesis and wound healing carry significant morbidity and mortality in diabetic patients. Metabolic stress from hyperglycemia and elevated free fatty acids have been shown to inhibit endothelial angiogenesis. However, the underlying mechanisms remain poorly understood. In this study, we show that dysregulation of the Hippo-YAP pathway, an important signaling in regulating tissue repair and regeneration, underlies palmitic acid (PA) -induced inhibition of endothelial angiogenesis. PA inhibited endothelial cell proliferation, migration and tube formation, which were associated with increased MST1 expression, YAP phosphorylation/inactivation and nuclear exclusion. Overexpression of YAP or knockdown of MST1 prevented PA-induced inhibition of angiogenesis. In searching upstream signaling, we found that PA dysregulated the Hippo-YAP pathway by inducing mitochondrial damage. PA treatment induced mitochondrial DNA (mtDNA) release to cytosol, and activated the cytosolic DNA sensor cGAS-STING-IRF3 signaling. Activated IRF3 bound to MST1 gene promoter and induced MST1 expression, leading to MST1 upregulation, YAP inactivation and angiogenesis inhibition. Thus, mitochondrial damage and the cytosolic DNA sensor cGAS-STING-IRF3 signaling are critically involved in PA-induced Hippo-YAP dysregulation and angiogenesis suppression. This mechanism may have implication in impairment of angiogenesis and wound healing in diabetes.

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