Mochin Maria T, Underwood Karen F, Cooper Brandon, McLenithan John C, Pierce Adam D, Nalvarte Cesar, Arbiser Jack, Karlsson Anna I, Moise Alexander R, Moskovitz Jackob, Passaniti Antonino
Department of Pathology, The University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biochemistry & Molecular Biology, The University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Medicine, The University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene & Stewart Greenebaum Cancer Center, The University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Dermatology, Emory University, Atlanta, GA, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA, USA.
Microvasc Res. 2015 Jan;97:55-64. doi: 10.1016/j.mvr.2014.09.008. Epub 2014 Oct 2.
Angiogenesis is regulated by hyperglycemic conditions, which can induce cellular stress responses, reactive oxygen species (ROS), and anti-oxidant defenses that modulate intracellular signaling to prevent oxidative damage. The RUNX2 DNA-binding transcription factor is activated by a glucose-mediated intracellular pathway, plays an important role in endothelial cell (EC) function and angiogenesis, and is a target of oxidative stress. RUNX2 DNA-binding and EC differentiation in response to glucose were conserved in ECs from different tissues and inhibited by hyperglycemia, which stimulated ROS production through the aldose reductase glucose-utilization pathway. Furthermore, the redox status of cysteine and methionine residues regulated RUNX2 DNA-binding and reversal of oxidative inhibition was consistent with an endogenous Methionine sulfoxide reductase-A (MsrA) activity. Low molecular weight MsrA substrates and sulfoxide scavengers were potent inhibitors of RUNX2 DNA binding in the absence of oxidative stress, but acted as antioxidants to increase DNA binding in the presence of oxidants. MsrA was associated with RUNX2:DNA complexes, as measured by a sensitive, quantitative DNA-binding ELISA. The related RUNX2 protein family member, RUNX1, which contains an identical DNA-binding domain, was a catalytic substrate of recombinant MsrA. These findings define novel redox pathways involving aldose reductase and MsrA that regulate RUNX2 transcription factor activity and biological function in ECs. Targeting of these pathways could result in more effective strategies to alleviate the vascular dysfunction associated with diabetes or cancer.
血管生成受高血糖条件调控，高血糖可诱导细胞应激反应、活性氧（ROS）及抗氧化防御，这些反应调节细胞内信号传导以防止氧化损伤。RUNX2 DNA结合转录因子由葡萄糖介导的细胞内途径激活，在内皮细胞（EC）功能和血管生成中起重要作用，且是氧化应激的靶点。在来自不同组织的内皮细胞中，RUNX2的DNA结合及对葡萄糖的内皮细胞分化反应是保守的，并受高血糖抑制，高血糖通过醛糖还原酶葡萄糖利用途径刺激ROS产生。此外，半胱氨酸和甲硫氨酸残基的氧化还原状态调节RUNX2的DNA结合，氧化抑制的逆转与内源性甲硫氨酸亚砜还原酶A（MsrA）活性一致。在无氧化应激时，低分子量MsrA底物和亚砜清除剂是RUNX2 DNA结合的有效抑制剂，但在有氧化剂存在时作为抗氧化剂增加DNA结合。通过灵敏的定量DNA结合ELISA检测发现，MsrA与RUNX2:DNA复合物相关。相关的RUNX2蛋白家族成员RUNX1含有相同的DNA结合结构域，是重组MsrA的催化底物。这些发现定义了涉及醛糖还原酶和MsrA的新型氧化还原途径，它们调节内皮细胞中RUNX2转录因子的活性和生物学功能。针对这些途径可能会产生更有效的策略来缓解与糖尿病或癌症相关的血管功能障碍。
