Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies
Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/3/556 |
| _version_ | 1827650101585117184 |
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| author | Gunther Marsche Julia T. Stadler Julia Kargl Michael Holzer |
| author_facet | Gunther Marsche Julia T. Stadler Julia Kargl Michael Holzer |
| author_sort | Gunther Marsche |
| collection | DOAJ |
| description | Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management. |
| first_indexed | 2024-03-09T20:10:44Z |
| format | Article |
| id | doaj.art-7991b32dedae4dfa8533936c970fdc22 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:10:44Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-7991b32dedae4dfa8533936c970fdc222023-11-24T00:18:44ZengMDPI AGAntioxidants2076-39212022-03-0111355610.3390/antiox11030556Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based TherapiesGunther Marsche0Julia T. Stadler1Julia Kargl2Michael Holzer3Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, AustriaOtto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, AustriaOtto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, AustriaOtto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, AustriaAtherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.https://www.mdpi.com/2076-3921/11/3/556myeloperoxidaseHDLpost-translational modificationparaoxonasecholesterol efflux capacity |
| spellingShingle | Gunther Marsche Julia T. Stadler Julia Kargl Michael Holzer Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies Antioxidants myeloperoxidase HDL post-translational modification paraoxonase cholesterol efflux capacity |
| title | Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies |
| title_full | Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies |
| title_fullStr | Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies |
| title_full_unstemmed | Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies |
| title_short | Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies |
| title_sort | understanding myeloperoxidase induced damage to hdl structure and function in the vessel wall implications for hdl based therapies |
| topic | myeloperoxidase HDL post-translational modification paraoxonase cholesterol efflux capacity |
| url | https://www.mdpi.com/2076-3921/11/3/556 |
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