title: Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair.
abstract: There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation.
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Olszewska-Pazdrak
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.
authors.forename: Scott D
authors.initials: SD
authors.lastname: McVicar
authors.affiliation: b Chrysalis BioTherapeutics, Inc., Galveston, Texas.
authors.forename: Kempaiah
authors.initials: K
authors.lastname: Rayavara
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Moya
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.|b Chrysalis BioTherapeutics, Inc., Galveston, Texas.
authors.forename: Carla
authors.initials: C
authors.lastname: Kantara
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.
authors.forename: Chris
authors.initials: C
authors.lastname: Gammarano
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.
authors.forename: Paulina
authors.initials: P
authors.lastname: Olszewska
authors.affiliation: b Chrysalis BioTherapeutics, Inc., Galveston, Texas.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Fuller
authors.affiliation: b Chrysalis BioTherapeutics, Inc., Galveston, Texas.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Sower
authors.affiliation: a Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas and.|b Chrysalis BioTherapeutics, Inc., Galveston, Texas.
authors.forename: Darrell H
authors.initials: DH
authors.lastname: Carney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology*; D016019:Survival Analysis; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D009569:Nitric Oxide; C412222:rusalatide acetate; D013917:Thrombin