ITF1697, a stable lys-pro-containing peptide, inhibits Weibel-Palade body exocytosis induced by ischemia/reperfusion and pressure elevation

Silvia Bertuglia, Hideo Ichimura, Gianluca Fossati, Kaushik Parthasarathi, Flavio Leoni, Daniela Modena, Piero Cremonesi, Jahar Bhattacharya, Paolo Mascagni

Research output: Contribution to journalArticle

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Abstract

A number of Lys-Pro-containing short peptides have been described as possessing a variety of biological activities in vitro. Because of limited metabolic stability, however, their efficacy in vivo is uncertain. To exploit the pharmacological potential of LysPro-containing short peptides, we synthesized a series of chemically modified forms of these peptides. One of them, ITF1697 (Gly(Nα-Et)Lys-Pro-Arg) was stable in vivo and particularly efficacious in experimental models of disseminated endotoxemia and of cardiovascular disorders. Using intravital fluorescence microscopy, we studied the peptide cellular and molecular basis of protection in the Syrian hamster cheek pouch microcirculation subjected to ischemia/reperfusion (I/R) and in pressure elevation-induced proinflammatory responses in isolated Sprague-Dawley rat lungs. Continuous intravenous infusion of ITF1697 at 0.1 to 100 μg/kg/min nearly completely protected the cheek pouch microcirculation from I/R injury as measured by decreased vascular permeability and increased capillary perfusion. Adhesion of leukocytes and platelets to blood vessels was strongly inhibited by the peptide. ITF1697 exerted its activity at the early stages of endothelial activation and inhibited P-selectin and von Willebrand factor secretion. Further mechanistic studies in the rat lung preparation revealed that the peptide inhibited the intracellular Ca2+-dependent fusion of Weibel-Palade bodies with the plasma membrane. The ability of ITF1697 to inhibit the early functions of activated endothelial cells, such as the exocytosis of Weibel-Palade bodies, represents a novel and promising pharmacological tool in model of pathologies of a variety of microvascular disorders.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalMolecular Medicine
Volume13
Issue number11-12
DOIs
StatePublished - Nov 1 2007

Fingerprint

lysylproline
Weibel-Palade Bodies
Exocytosis
Reperfusion
Ischemia
Pressure
Peptides
Cheek
Microcirculation
Pharmacology
Lung
P-Selectin
Endotoxemia
Mesocricetus
von Willebrand Factor
Capillary Permeability
Reperfusion Injury
Fluorescence Microscopy
Intravenous Infusions
Blood Vessels

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

ITF1697, a stable lys-pro-containing peptide, inhibits Weibel-Palade body exocytosis induced by ischemia/reperfusion and pressure elevation. / Bertuglia, Silvia; Ichimura, Hideo; Fossati, Gianluca; Parthasarathi, Kaushik; Leoni, Flavio; Modena, Daniela; Cremonesi, Piero; Bhattacharya, Jahar; Mascagni, Paolo.

In: Molecular Medicine, Vol. 13, No. 11-12, 01.11.2007, p. 615-624.

Research output: Contribution to journalArticle

Bertuglia, S, Ichimura, H, Fossati, G, Parthasarathi, K, Leoni, F, Modena, D, Cremonesi, P, Bhattacharya, J & Mascagni, P 2007, 'ITF1697, a stable lys-pro-containing peptide, inhibits Weibel-Palade body exocytosis induced by ischemia/reperfusion and pressure elevation', Molecular Medicine, vol. 13, no. 11-12, pp. 615-624. https://doi.org/10.2119/2007-00079.Bertuglia
Bertuglia, Silvia ; Ichimura, Hideo ; Fossati, Gianluca ; Parthasarathi, Kaushik ; Leoni, Flavio ; Modena, Daniela ; Cremonesi, Piero ; Bhattacharya, Jahar ; Mascagni, Paolo. / ITF1697, a stable lys-pro-containing peptide, inhibits Weibel-Palade body exocytosis induced by ischemia/reperfusion and pressure elevation. In: Molecular Medicine. 2007 ; Vol. 13, No. 11-12. pp. 615-624.
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AU - Parthasarathi, Kaushik

AU - Leoni, Flavio

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