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 Lys-Pro-containing short peptides, we synthesized a series of chemically modified forms of these peptides. One of them, ITF1697 (Gly-(Nalpha-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 mug/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 Ca(2+)-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.
Highlights
Several biologically active small peptides contain the Lys-Pro motif at the core of their sequence
In this study, we show that ITF1697, a metabolically stabilized tetrapeptide of sequence Gly-(Nα-Et)Lys-Pro-Arg, is highly efficacious in reducing microvascular inflammation and platelet aggregation in two models of microvascular injury, namely ischemia/ reperfusion (I/R) in the hamster cheek pouch and high-pressure–induced endothelial activation in isolated rat lung preparations
Reperfusion following ischemia is characterized by inflammatory responses in which P-selectin–dependent leukocyte recruitment occurs in the postcapillary venules [25,26,27,28]
Summary
Several biologically active small peptides contain the Lys-Pro motif at the core of their sequence. They include tuftsin (Thr-Lys-Pro-Arg), a γ-globulin derived tetrapeptide that stimulates phagocytosis [1]; another tetrapeptide of sequence Gly-Lys-Pro-Val, which corresponds to the C-terminal region of αMSH and is endowed with anti-inflammatory properties [2]; and the interleukin-1β–derived tripeptide Lys-ProThr, which partially antagonizes the hyperalgesic effect of the parent molecule [3]. Synthetic LysPro–containing peptides (for example, Thr-Lys-Pro-Leu, Gly-Lys-Pro-Arg, and Thr-Lys-Pro-Gln) derived from the sequence of C-reactive protein (CRP), the prototypic acute-phase protein in humans, were shown to possess biological activity [4,5]. The peptide mechanism of action is not known, evidence has accumulated indicating that cell tissue infiltration is largely inhibited in the presence of ITF1697
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