title: Hyperglycemia and redox status regulate RUNX2 DNA-binding and an angiogenic phenotype in endothelial cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Mochin
authors.affiliation: 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.
authors.forename: Karen F
authors.initials: KF
authors.lastname: Underwood
authors.affiliation: 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.
authors.forename: Brandon
authors.initials: B
authors.lastname: Cooper
authors.affiliation: 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.
authors.forename: John C
authors.initials: JC
authors.lastname: McLenithan
authors.affiliation: 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.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Pierce
authors.affiliation: 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.
authors.forename: Cesar
authors.initials: C
authors.lastname: Nalvarte
authors.affiliation: Department of Dermatology, Emory University, Atlanta, GA, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.affiliation: Department of Dermatology, Emory University, Atlanta, GA, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA, USA.
authors.forename: Anna I
authors.initials: AI
authors.lastname: Karlsson
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moise
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Jackob
authors.initials: J
authors.lastname: Moskovitz
authors.affiliation: 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; The Veteran's Health Administration Research & Development Service, Baltimore, MD, USA. Electronic address: apass001@umaryland.edu.
authors.forename: Antonino
authors.initials: A
authors.lastname: Passaniti
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism; D009389:Neovascularization, Pathologic; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D016877:Oxidants; C493728:RUNX1 protein, human; C493709:RUNX2 protein, human; D004247:DNA; D000449:Aldehyde Reductase; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D005947:Glucose
keywords: Angiogenesis; Antioxidant enzymes; Endothelial cell differentiation; Oxidative stress; Transcriptional factors