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GSaggu PhD Thesis_2014.pdf (10.52 MB)

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Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates

Saggu, Gurpanna
http://rave.ohiolink.edu/etdc/view?acc_num=mco1392998532

Abstract Details

2014, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
Patients with inflammatory cardiovascular disease have an increased number of circulating activated platelets and platelet-leukocyte aggregates (PLAs), both of which play a central role in the initiation and progression of disease. Activated platelets can activate the complement system on their surface, with potential consequences in vascular inflammation and thrombosis. Properdin, a positive regulator of the alternative pathway (AP) of complement, is produced mainly by stimulated leukocytes. The mechanisms by which properdin participates in complement activation on platelets and in PLA formation remain unknown. We have shown that the physiological forms of human properdin bind directly to activated, but not resting, platelets. The binding of properdin promotes AP complement activation on activated platelets, as measured by C3b and C9 deposition on their surface, by forming novel C3 convertases on the platelet [C3(H2O),Bb]. Removal of surface proteins by treating platelets with a low dose of proteinase K, leads to reduced properdin binding to activated platelets. On the other hand, chondroitin sulfate-A (a glycosaminoglycan that is released by platelets upon activation) increases the binding of properdin to activated platelets by ~4 fold. These results suggest that interaction of properdin with activated platelets may depend on a protein receptor as well as glycosaminoglycans (i.e. proteoglycans). We have also determined that properdin released by PMA-stimulated neutrophils binds to activated platelets. Since activated neutrophils and platelets directly interact with one another in pro-inflammatory microenvironments, the fresh properdin produced by neutrophils would be available to platelets at high concentrations. Using ex-vivo whole blood assays, we show that properdin leads to an increase in PLA formation in TRAP (thrombin receptor activating peptide)-stimulated whole blood and inhibition of properdin leads to decrease in PLA formation. Our data also show that properdin-mediated PLA formation is controlled by complement regulatory protein factor H. Altogether, the results support a role for properdin in the cellular microenvironment, contributing to complement activation on activated platelets and PLA formation, with potential consequences in inflammation pathophysiology.
Viviana Ferreira, D.V.M., Ph.D. (Advisor)
Stanislaw Stepkowski, D.V.M., Ph.D. (Committee Member)
Mark Wooten, Ph.D. (Committee Member)
Kevin Pan, M.D., Ph.D. (Committee Member)
Guillermo Vazquez, Ph.D. (Committee Member)
210 p.
Biology; Biomedical Research; Immunology
platelets, complement, alternative pathway, properdin, factor H, platelet-leukocyte aggregates

Recommended Citations

Citations

  • Saggu, G. (2014). Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1392998532

    APA Style (7th edition)

  • Saggu, Gurpanna. Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates. 2014. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1392998532.

    MLA Style (8th edition)

  • Saggu, Gurpanna. "Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates." Doctoral dissertation, University of Toledo, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1392998532

    Chicago Manual of Style (17th edition)

mco1392998532
524
© 2014, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.
Release 3.2.12