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Human platelet aggregation induced via protease-activated receptor 1 (PAR1)signaling is reversed by nitric oxide (NO) through inhibition of a Rho-kinase/ROCK-mediated pathway
Linköping University, Department of Physics, Chemistry and Biology.
2010 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Human platelets are constantly regulated by activating and inhibitory effectors. Thrombin,the most potent platelet agonist, induces signaling through the protease-activated receptors(PARs) 1 and 4 which in turn convey their signal by coupling to G-proteins. Nitric oxide (NO)is a potent platelet inhibitor continuously formed by the endothelium exerting its effect byincreasing cGMP through activation of soluble guanylyl cyclase (sGC). The purpose of thiswork has been to investigate how NO would affect platelets already activated by PARagonists.To examine the different contributions of the PAR1- and PAR4-signals, the selectiveagonist peptides SFLLRN and AYPGKF-NH2 were utilized. Aggregation, Ca2+-mobilization andphosphorylation of threonine 696 in myosin phosphatase target subunit 1 (MYPT1) wereanalyzed. Intriguingly PAR1-, but not PAR4-, agonist provoked aggregation was rapidlyreversed upon NO exposure. PAR-agonist induced Ca2+-mobilization was markedly reducedafter exposure to NO, however this Ca2+-suppression did not cause the disaggregation ofPAR1-agonist evoked platelet aggregation. The reversal of aggregation was suspected to becaused by a cGMP-mediated inhibition of the Rho-kinase/ROCK-signaling pathway. This wassupported by Westen blot analysis where a marked decrease of MYPT1 phosphorylationcompared to basal levels could be observed. In conclusion, NO was found to reverse humanplatelet aggregation evoked by PAR1-activation by inhibition of a Rho-kinase/ROCK-signalingpathway.

Place, publisher, year, edition, pages
2010. , 24 p.
Keyword [en]
Platelet, nitric oxide, PAR1, Rho-kinase, ROCK
National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-60742ISRN: LITH-IFM-A--EX--10/2365--SEOAI: diva2:358920
Available from: 2010-10-26 Created: 2010-10-25 Last updated: 2010-10-26Bibliographically approved

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