Abstract 451: Enrichment Of High Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression
| Autor: | Maura Mobilia, Callie Whitus, Alexander Karakashian, Scott M Gordon |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 42 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.42.suppl_1.451 |
| Popis: | Background: Atherosclerotic lesions contain inflammatory cells which secrete a variety of proteolytic enzymes that contribute to lesion progression. The relative contributions of specific proteases to lesion progression is not well understood. The serine protease elastase is produced by neutrophils and macrophages in atherosclerotic lesions and may contribute to plaque progression and destabilization. We have reported significant enrichment of protease inhibitor proteins associated with plasma high density lipoprotein (HDL), including the elastase inhibitor alpha-1-antitrypsin, suggesting a potential role for HDL as an endogenous modulator of protease activity. Hypothesis: We hypothesized that protease inhibition is a mechanism for HDL-mediated protection against atherosclerosis that is independent of HDL cholesterol content. Methods and Results: We developed an HDL-targeting protease inhibitor (HTPI) peptide to allow for synthetic enrichment of HDL-associated elastase inhibitor activity. The small (1 kDa) peptide has an HDL-targeting domain, a soluble linker, and an elastase inhibitor motif. Using a fluorescent version, we demonstrated preferential binding to HDL in human plasma ex vivo . When injected into mice, we observed binding to plasma HDL and increased elastase inhibitor activity on HDL isolated from plasma of mice that received HTPI. Injection into mouse models of atherosclerosis resulted in accumulation of HTPI within lesions. To examine the impact of HTPI treatment on established atherosclerosis, Ldlr -/- mice were maintained on Western diet for 12 weeks, then administered vehicle or HTPI (2.5 mg/kg) three times per week for two weeks while remaining on diet. Lesion quantification by en face analysis and aortic root sections demonstrated that HTPI prevented additional lipid deposition in established lesions. The impact of HTPI on lesion morphology and inflammatory features was examined by histology and immunofluorescence staining of aortic root sections. Conclusions: Targeted enrichment of HDL-associated elastase inhibitor activity using a synthetic peptide prevented atherosclerotic lesion progression. These findings support a possible role for the endogenous antiprotease activity of HDL in atheroprotection. |
| Databáze: | OpenAIRE |
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