Platelet aggregation and acute inflammation are key processes in vertebrate defense to a skin injury. Recent studies uncovered the mediation of 2 serine proteases, cathepsin G and chymase, in both mechanisms. Working with a mouse model of acute inflammation, we revealed that an exogenous salivary protein of Ixodes ricinus, the vector of Lyme disease pathogens in Europe, extensively inhibits edema formation and influx of neutrophils in the inflamed tissue. We named this tick salivary gland secreted effector as I ricinus serpin-2 (IRS-2), and we show that it primarily inhibits cathepsin G and chymase, while in higher molar excess, it affects thrombin activity as well. The inhibitory specificity was explained using the crystal structure, determined at a resolution of 1.8 Å. Moreover, we disclosed the ability of IRS-2 to inhibit cathepsin G-induced and thrombin-induced platelet aggregation. For the first time, an ectoparasite protein is shown to exhibit such pharmacological effects and target specificity. The stringent specificity and biological activities of IRS-2 combined with the knowledge of its structure can be the basis for the development of future pharmaceutical applications.
- MeSH
- agregace trombocytů genetika imunologie MeSH
- chymasy imunologie metabolismus MeSH
- exprese genu MeSH
- hmyzí proteiny genetika imunologie metabolismus MeSH
- kathepsin G imunologie metabolismus MeSH
- klíště genetika imunologie metabolismus MeSH
- krystalizace MeSH
- kvarterní struktura proteinů MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- molekulární sekvence - údaje MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- sekvence aminokyselin MeSH
- sekvenční analýza proteinů MeSH
- serpiny genetika imunologie metabolismus MeSH
- slinné proteiny a peptidy genetika imunologie metabolismus MeSH
- zánět imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chymasy MeSH
- hmyzí proteiny MeSH
- kathepsin G MeSH
- serpin-2 MeSH Prohlížeč
- serpiny MeSH
- slinné proteiny a peptidy MeSH
To define better the relationships between lipid metabolism disturbances and platelet aggregation we have examined these parameters in hereditary hypertriglyceridemic and control Lewis rats. Hereditary hypertriglyceridemic rats are hypertensive and have high plasma triglycerides but not elevated plasma total cholesterol. In the present study, we have demonstrated that platelets from hereditary hypertriglyceridemic rats have lowered initial rate and maximal aggregation after stimulation with thrombin or ADP in comparison with controls. These two strains did not differ significantly in the inhibition of platelet aggregation by the thromboxane A2 receptor inhibitor, SQ 29 548. In hereditary hypertriglyceridemic rats, the thrombin response, as well as the contribution of the thromboxane A2-sensitive pathway, were positively associated with the plasma level of triglycerides. Similar trend was found in Lewis rats. However, the slopes of these relationships were reduced in hereditary hypertriglyceridemic rats. These alterations of the aggregatory responses in hereditary hypertriglyceridemic rats were independent of blood pressure and plasma cholesterol level. In conclusion, our results showed a clear-cut platelet hypoaggregability to both thrombin and ADP in hypertensive hypertriglyceridemic rats. This hypoaggregability was not due to an impaired function of the thromboxane A2 pathway but could be connected with disturbances of lipid metabolism.
- MeSH
- adenosindifosfát farmakologie MeSH
- agregace trombocytů účinky léků genetika fyziologie MeSH
- bicyklické sloučeniny heterocyklické MeSH
- hydraziny farmakologie MeSH
- hypertenze krev komplikace genetika MeSH
- hypertriglyceridemie krev komplikace genetika MeSH
- kinetika MeSH
- krysa rodu Rattus MeSH
- nenasycené mastné kyseliny MeSH
- potkani inbrední LEW MeSH
- receptory thromboxanů antagonisté a inhibitory MeSH
- triglyceridy krev MeSH
- trombin farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenosindifosfát MeSH
- bicyklické sloučeniny heterocyklické MeSH
- hydraziny MeSH
- nenasycené mastné kyseliny MeSH
- receptory thromboxanů MeSH
- SQ 29548 MeSH Prohlížeč
- triglyceridy MeSH
- trombin MeSH
OBJECTIVE: Hyper-responsive platelets are often found in essential hypertension. It has also been suggested that in hypertensive patients platelets may serve as an easily accessible indicator of abnormalities in contractile cell function. To test these suggestions, we analysed the relationship between platelet aggregation and genetic hypertension in the rat. METHODS: Linear regression analysis of mean values of recombinant inbred strains was used to evaluate the relationship between blood pressure and ADP-induced platelet aggregation. RESULTS: ADP-induced platelet aggregation in platelet-rich plasma in spontaneously hypertensive rats (SHR) was significantly decreased compared with in normotensive Brown Norway (BN) rats. However, in recombinant inbred strains, derived from (SHR x BN) F2 hybrids, correlation analysis revealed that platelet aggregation and blood pressure are independent traits. CONCLUSIONS: The present results suggest strongly that spontaneous hypertension and platelet hypo-aggregability in SHR were linked together by chance due to drift during selective inbreeding. The absence of a correlation between the two traits also indicates that alterations in platelet function in essential hypertension, often found in population-based studies, may have to be reaffirmed in genetically better-defined situations, e.g. by pedigree analysis.
- MeSH
- agregace trombocytů genetika MeSH
- hybridizace genetická genetika fyziologie MeSH
- hypertenze genetika patofyziologie MeSH
- krevní tlak genetika fyziologie MeSH
- krysa rodu Rattus MeSH
- lineární modely MeSH
- potkani inbrední BN fyziologie MeSH
- potkani inbrední SHR fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
