Yuan Liangshuai, Mao Yun, Luo Wei, Wu Weiwei, Xu Hao, Wang Xing Li, Shen Ying H
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research.
the Qilu Hospital of Shandong University, Jinan 250012, China.
J Biol Chem. 2017 Sep 8;292(36):15002-15015. doi: 10.1074/jbc.M117.804005. Epub 2017 Jul 11.
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-Yes-associated protein (YAP) pathway, an important signaling mechanism 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 expression of mammalian Ste20-like kinases 1 (MST1), YAP phosphorylation/inactivation, and nuclear exclusion. Overexpression of YAP or knockdown of MST1 prevented PA-induced inhibition of angiogenesis. When searching upstream signaling mechanisms, we found that PA dysregulated the Hippo-YAP pathway by inducing mitochondrial damage. PA treatment induced mitochondrial DNA (mtDNA) release to cytosol, and activated cytosolic DNA sensor cGAS-STING-IRF3 signaling. Activated IRF3 bound to the gene promoter and induced MST1 expression, leading to MST1 up-regulation, YAP inactivation, and angiogenesis inhibition. Thus, mitochondrial damage and 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.
血管生成受损和伤口愈合不良在糖尿病患者中具有显著的发病率和死亡率。高血糖和游离脂肪酸升高引起的代谢应激已被证明会抑制内皮细胞血管生成。然而，其潜在机制仍知之甚少。在本研究中，我们发现，作为调节组织修复和再生的重要信号机制，Hippo-Yes相关蛋白（YAP）通路失调是棕榈酸（PA）诱导的内皮细胞血管生成抑制的基础。PA抑制内皮细胞增殖、迁移和管腔形成，这与哺乳动物Ste20样激酶1（MST1）表达增加、YAP磷酸化/失活及核排除有关。YAP过表达或MST1敲低可防止PA诱导的血管生成抑制。在探寻上游信号机制时，我们发现PA通过诱导线粒体损伤使Hippo-YAP通路失调。PA处理诱导线粒体DNA（mtDNA）释放到细胞质中，并激活细胞质DNA传感器cGAS-STING-IRF3信号通路。激活的IRF3与 基因启动子结合并诱导MST1表达，导致MST1上调、YAP失活和血管生成抑制。因此，线粒体损伤和细胞质DNA传感器cGAS-STING-IRF3信号通路在PA诱导的Hippo-YAP失调和血管生成抑制中起关键作用。这一机制可能与糖尿病患者血管生成受损和伤口愈合不良有关。
