title: The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis.
abstract: Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19-2.5 belongs to the class of synthetic anti-lipopolysaccharide peptides; however, its activity is not restricted to Gram-negative bacterial infection. We hypothesized that peptide 19-2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19-2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19-2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19-2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19-2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19-2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19-2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19-2.5 seems to be a potential anti-inflammatory agent in sepsis.
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Martin
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: De Santis
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Koczera
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Simons
authors.affiliation: Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany.
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH, Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schuerholz
mesh_terms: D000328:Adult; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D000890:Anti-Infective Agents; D005966:Glucuronidase; D006497:Heparan Sulfate; D010455:Peptides; D000099175:Heparanase