Abstract
Background and aims: Inflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high- density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as a modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression.
Methods: We designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis were examined using mouse models. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features.
Results: HTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL- targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after administration to Apoe / mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr / mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque.
Conclusions: These data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.
Document Type
Article
Publication Date
9-2024
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.atherosclerosis.2024.118544
Funding Information
This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute R01HL171111 (S.M.G) and K22HL141299 (S.M.G), National Institute on Aging R01AG080589 (L.A. J, S.M.G), the Harold S. Geneen Charitable Trust Awards Program for Coronary Heart Disease Research (S.M.G), and the Alpha-1 Foundation (S.M.G). Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30GM127211.
Repository Citation
Mobilia, Maura; Karakashian, Alexander A.; Neupane, Khaga R.; Hage, Olivia; Whitus, Callie; Carter, Abigail; Voy, Clairity; Johnson, Lance A.; Graf, Gregory A.; and Gordon, Scott M., "Enhancement of high-density lipoprotein-associated protease inhibitor activity prevents atherosclerosis progression" (2024). Saha Cardiovascular Research Center Faculty Publications. 80.
https://uknowledge.uky.edu/cvrc_facpub/80
Notes/Citation Information
0021-9150/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by- nc/4.0/).