The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis

• Published in: PloS one 2015-11, Vol.10 (11), p.e0143583-e0143583
• Main Authors: Martin, Lukas, De Santis, Rebecca, Koczera, Patrick, Simons, Nadine, Haase, Hajo, Heinbockel, Lena, Brandenburg, Klaus, Marx, Gernot, Schuerholz, Tobias
• Format: Article
• Language: English
• Subjects: Adult; Animal sciences; Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - therapeutic use; Bacteria; Biophysics; Biotechnology; Calorimetry; Cancer therapies; Comparative analysis; Diagnosis; Enzyme-Linked Immunosorbent Assay; Exothermic reactions; Fragmentation; Fragments; Glucuronidase - metabolism; Gram-negative bacteria; Gram-positive bacteria; Health aspects; Heparan sulfate; Heparitin Sulfate - metabolism; Hospitals; Humans; Inflammation; Inflammatory response; Intensive care; Kidneys; Laboratory animals; Lipopolysaccharides; Liver; Lungs; Medical research; Mice; mRNA; Peptides; Peptides - chemical synthesis; Peptides - therapeutic use; Physiology; Plasma; Proteoglycans; Sepsis; Sepsis - drug therapy; Sepsis - enzymology; Sepsis - metabolism; Septic shock; Spleen; Studies; Sulfates; Titration; Titration calorimetry; Zoology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143583

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.