Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation

Journal of Thrombosis and Haemostasis : JTH
H AkbarY Zheng

Abstract

Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1-p67phox interaction prevents platelet activation. Pharmacologic targeting of Rac1-NOX2 axis can be a viable approach for antithrombotic therapy. Background Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. Objective We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac-p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1-/- mice or human platelets treated with NSC23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP. Treatment of platelets with Phox-I inhibited diverse CR...Continue Reading

References

Jan 1, 1977·The Journal of Clinical Investigation·A J MarcusH L Ullman
May 1, 1977·The Journal of Clinical Investigation·R I HandinG J Boxer
Feb 1, 1993·Proceedings of the National Academy of Sciences of the United States of America· Huzoor-AkbarJ B Stock
Nov 25, 2000·Molecular Cell·K LapougeK Rittinger
Feb 27, 2001·Nature Immunology·B A Diebold, G M Bokoch
Sep 13, 2001·Thrombosis Research·T SenoM Yokoyama
Nov 8, 2003·Arteriosclerosis, Thrombosis, and Vascular Biology·Patricia CluttonJane E Freedman
Nov 18, 2003·The Journal of Clinical Investigation·Beatrice CambienDenisa D Wagner
May 7, 2004·Proceedings of the National Academy of Sciences of the United States of America·Yuan GaoYi Zheng
Jul 10, 2004·Antioxidants & Redox Signaling·Stefan ChlopickiJacek Miedzobrodzki
Jul 14, 2004·Circulation·P PignatelliF Violi
Sep 18, 2004·Arteriosclerosis, Thrombosis, and Vascular Biology·Florian KrötzUlrich Pohl
Jul 19, 2005·Nature Medicine·Jose A CancelasDavid A Williams
Oct 1, 2005·The Journal of Biological Chemistry·Owen J T McCartySteve P Watson
Feb 14, 2006·Methods in Enzymology·Huzoor AkbarYi Zheng
Apr 26, 2006·The Journal of Biological Chemistry·Guangjie ChengJ David Lambeth
Jan 24, 2007·Physiological Reviews·Karen Bedard, Karl-Heinz Krause
Aug 25, 2009·The Journal of Biological Chemistry·Soochong KimSatya P Kunapuli
Nov 13, 2010·Arteriosclerosis, Thrombosis, and Vascular Biology·Pasquale PignatelliFrancesco Violi
Jan 10, 2014·Thrombosis and Haemostasis·Francesco Violi, Pasquale Pignatelli
Jun 29, 2014·Journal of the American Heart Association·Roberto CarnevaleFrancesco Violi
Dec 3, 2014·Journal of Thrombosis and Haemostasis : JTH·T M GetzW Bergmeier
Apr 8, 2015·Prostaglandins & Other Lipid Mediators·Daniele PastoriFrancesco Violi
Mar 11, 2016·Thrombosis and Haemostasis·Simona BartimocciaFrancesco Violi
Mar 19, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·M Keegan DelaneyXiaoping Du
Aug 11, 2017·Blood·Tom N DurrantIngeborg Hers
Sep 9, 2017·Arteriosclerosis, Thrombosis, and Vascular Biology·Yangyang LiuHu Hu

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Citations

Aug 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dina VaraGiordano Pula
Jul 15, 2020·International Journal of Molecular Sciences·Elena MasselliGiuliana Gobbi
Mar 12, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Zheng XuXiaoping Du
Jun 29, 2021·Frontiers in Cardiovascular Medicine·Lulu AnPoornima Venkat

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