# Serpin Regulation of Coagulation Proteases

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $431,612

## Abstract

Project Summary
Antithrombin (AT) is a major serpin inhibitor in plasma that regulates the proteolytic activity of
coagulation proteases of intrinsic and extrinsic pathways. In addition to its anticoagulant function, AT
also has a potent antiinflammatory function. The anticoagulant function of AT is mediated through its
reactive center loop (RCL)-dependent inhibition of coagulation proteases, but the antiinflammatory
signaling function of AT is mediated via its D-helix-dependent interaction with glycosaminoglycan
(GAG) chains, attached to core proteins of heparan sulfate proteoglycans (HSPGs). Unlike the
relatively well-understood anticoagulant function, the mechanism of the antiinflammatory function of
AT is poorly understood. Moreover, because it is thought that a conformational change in the RCL of
AT by D-helix-dependent interaction with vascular GAGs is required for the protease inhibitory
function of the serpin, the contribution of the AT D-helix-GAG interaction to the physiological function
of the serpin in two pathways remains unknown. The antiinflammatory function of AT requires its D-
helix dependent interaction with 3-O-sulfate (3-OS) containing GAGs, the same type of vascular
GAGs which are thought to be required for the conformational activation of AT in order for the serpin
to optimally inhibit the activity of vitamin K-dependent coagulation proteases. The Syndecan-4
(Synd-4) sub-family of HSPGs has been identified as the primary receptor on which AT binds to elicit
antiinflammatory responses in vascular endothelial cells. However, Synd-4 is also an essential co-
receptor for receptor tyrosine kinases for signaling by basic fibroblast growth factor (FGF2 also
called bFGF) in vascular endothelial cells. The mechanism by which AT and FGF2 utilize the same
receptor to elicit paradoxical signaling responses is completely unknown. We have prepared several
AT and receptor mutants and propose to investigate these questions, employing both cellular and
animal models in 2 Specific Aims. We propose to investigate 1) the significance of AT D-helix
interaction with vascular HSPGs to the physiological function of the serpin, in the alternative
anticoagulant and antiinflammatory pathways by employing AT-deficient mice and 2) the mechanism
by which AT elicits intracellular signaling responses in vascular endothelial cells. A sub-aim of Aim 2
will investigate the mechanism by which cleaved and/or latent AT elicit antiangiogenic responses in
endothelial cells in response to FGF2. These studies will utilize multidisciplinary approaches
including genetics, basic biochemistry, kinetics, cellular and molecular biology methods to provide
key information related to the D-helix dependent antiinflammatory signaling mechanism of AT.

## Key facts

- **NIH application ID:** 9900845
- **Project number:** 5R01HL062565-22
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** ALIREZA R. REZAIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,612
- **Award type:** 5
- **Project period:** 1999-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900845

## Citation

> US National Institutes of Health, RePORTER application 9900845, Serpin Regulation of Coagulation Proteases (5R01HL062565-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9900845. Licensed CC0.

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