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Synthetic lipopeptide Pam3CysSer(Lys)4 is an effective activator of human platelets
M Berg1, S Offermanns, R Seifert
1Institut für Pharmakologie, Freie Universität Berlin, Germany.
Abstract:
Lipopeptide analogues of the NH2-terminus of bacterial lipoprotein are known to induce activation of macrophages, neutrophils, and lymphocytes. We studied the effect of the lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-( S)-seryl-(S)-lysyl-(S)-lysyl-(S)-lysyl-(S)-lysine [Pam3CysSer(Lys)4] on several functions of human platelets. Pam3CysSer(Lys)4 led to the aggregation of platelets and induced the secretion of serotonin with an effectiveness similar to thrombin. These cellular effects of Pam3CysSer(Lys)4 were concentration dependent, being half maximal at 2-3 microM and maximal at 10-30 microM. Another lipopeptide also induced platelet aggregation and serotonin secretion but was less potent and less effective than Pam3CysSer(Lys)4. The lipid moiety and the peptide moiety of Pam3CysSer(Lys)4 alone were without any effect. Lipopeptides also stimulated tyrosine phosphorylation of several proteins with molecular masses similar to those found to be tyrosine phosphorylated in response to thrombin, and Pam3CysSer(Lys)4 led to an increase in the cytosolic calcium concentration. All studied responses of platelets to lipopeptides were inhibited by the prostacyclin receptor agonist cicaprost. Taken together, our data show that lipopeptides are effective activators of human platelets and that this activation is susceptible to the action of physiological platelet inhibitors.
Insights
Lipopeptides, like Pam3CysSer(Lys)4, activate human platelets, causing aggregation and serotonin release. This platelet activation by lipopeptides can be inhibited by physiological platelet inhibitors.
Area of Science:
- Immunology
- Biochemistry
- Hematology
Background:
- Lipopeptide analogues of bacterial lipoprotein activate immune cells.
- The role of lipopeptides in human platelet function is not fully understood.
Purpose of the Study:
- To investigate the effects of the lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-(S)-seryl-(S)-lysyl-(S)-lysyl-(S)-lysyl-(S)-lysine [Pam3CysSer(Lys)4] on human platelet functions.
- To determine the mechanisms underlying lipopeptide-induced platelet activation.
Main Methods:
- Studied platelet aggregation, serotonin secretion, tyrosine phosphorylation, and cytosolic calcium concentration in response to lipopeptides.
- Utilized concentration-dependent assays and employed the prostacyclin receptor agonist cicaprost for inhibition studies.
Main Results:
- Pam3CysSer(Lys)4 induced platelet aggregation and serotonin secretion comparable to thrombin.
- Lipopeptides stimulated tyrosine phosphorylation and increased cytosolic calcium levels.
- Platelet responses to lipopeptides were inhibited by cicaprost.
Conclusions:
- Lipopeptides are potent activators of human platelets.
- Lipopeptide-induced platelet activation involves signaling pathways similar to thrombin and is modulated by physiological inhibitors like prostacyclin.