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Small molecule targeting the Rac1‐NOX2 interaction prevents collagen‐related peptide and thrombin‐induced reactive oxygen species generation and platelet activation
Author(s): ,
H. Akbar
Affiliations:
Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, USA
Correspondence: Huzoor Akbar, Department of Biomedical Sciences, 416 Irvine Hall, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA|Tel.: +1 740 593 2406|E‐mail: akbar@ohio.edu
,
X. Duan
Affiliations:
Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USA
,
R. Piatt
Affiliations:
McAllister Heart Institute, University of North Carolina, Chapel Hill, USA
,
S. Saleem
Affiliations:
Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, USA
,
A. K. Davis
Affiliations:
Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USA
,
N. N. Tandon
Affiliations:
Cellphire Inc., Rockville, USA
,
W. Bergmeier
Affiliations:
McAllister Heart Institute, University of North Carolina, Chapel Hill, USA
Y. Zheng
Affiliations:
Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USA
ISTH Academy. Akbar H. Oct 4, 2018; 234165
Dr. Huzoor Akbar
Dr. Huzoor Akbar

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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 p67 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–p67 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 CRP‐induced responses, including: (i) ROS generation; (ii) release of P‐selectin; (iii) secretion of ATP; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox‐I inhibited thrombin‐induced: (i) secretion of ATP; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox‐I inhibited: (i) collagen‐induced platelet aggregation without affecting the tail bleeding time and (ii) in vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss.
Conclusions
Small molecule targeting of the Rac1–p67 interaction may present an antithrombosis regimen by preventing GPVI‐ and non‐GPVI‐mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time.
Keyword(s)
NADPH oxidase, platelet activation, Rac1 GTP‐binding protein, reactive oxygen species, thrombosis
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