# Functional Interactions Between Lipoproteins and Protease Inhibitors in Atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $641,168

## Abstract

Project Summary
Lipoproteins are dynamic complexes of lipid and protein in the circulation that are correlated with
cardiovascular events. Lipoprotein particles can interact with over 100 different proteins in the
circulation. However, except for a few core lipid-binding proteins (apolipoproteins), the functional
implications of these protein-lipoprotein interactions are not known. We found that about 20% of
lipoprotein-associated proteins are protease inhibitors. Proteases are enzymes that cleave other
proteins and they play important roles in many physiological pathways. In atherosclerosis, their activity
is often associated with inflammation and unstable lesions that may be more prone to rupture. Because
lipoproteins accumulate within atherosclerotic lesions and these particles are enriched with protease
inhibitors, we propose that lipoprotein-associated protease inhibitor activity may be a novel mechanism
by which lipoproteins can suppress vascular inflammation and stabilize atherosclerotic lesions.
 Alpha-1-antitrypsin (AAT) is an abundant plasma serine protease inhibitor that is detected on
both low density and high-density lipoproteins (LDL and HDL, respectively). AAT is an endogenous
inhibitor of neutrophil elastase, a protease generated by neutrophils and macrophages within
atherosclerotic lesions. Our central hypothesis is that lipoproteins can modulate AAT function and this
contributes to lipoprotein-mediated effects on atherosclerosis by influencing vascular inflammation. Our
preliminary data suggest a unique structural interaction between AAT and lipoproteins that results in
functional preservation of AAT activity. Aim 1 of our proposal will investigate this structure-function
interaction in detail and will determine the mechanistic basis for this observation on LDL and HDL.
These studies will utilize cross-liking mass spectrometry and detailed in vitro functional assays. The
literature and our preliminary data support a potential role of AAT in various cardiovascular diseases,
however, the mechanistic contribution of AAT to vascular inflammation in atherosclerosis has not been
studied. Aim 2 will determine the role of lipoprotein-associated elastase-inhibitor activity in vascular
inflammation and atherosclerosis using in vivo mouse models of atherosclerosis. Furthermore, we have
developed a novel lipoprotein-targeting elastase-inhibitor peptide for synthetic enhancement of
lipoprotein-associated protease inhibitor activity. Aim 3 will utilize a newly generated AAT-deficient
mouse model to examine the impact of AAT on hepatic lipid metabolism and atherosclerosis. Together,
these studies will fill a significant knowledge gap in our understanding of how non-apolipoprotein
components of lipoproteins can impact atherosclerosis risk by modulating the antiinflammatory potential
of lipoproteins. This work will also develop new tools for enhancement of lipoprotein function and data
on the potential of this approach for atherosclerosis preven...

## Key facts

- **NIH application ID:** 10979839
- **Project number:** 1R01HL171111-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Scott M Gordon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,168
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979839

## Citation

> US National Institutes of Health, RePORTER application 10979839, Functional Interactions Between Lipoproteins and Protease Inhibitors in Atherosclerosis (1R01HL171111-01A1). Retrieved via AI Analytics 2026-07-24 from https://api.ai-analytics.org/grant/nih/10979839. Licensed CC0.

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