Journal article
Lipoprotein(a) and vascular redox state in patients with advanced coronary atherosclerosis
- Abstract:
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Background: Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redoxsensitive inflammatory state.
Methods: Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease (CAD) undergoing cardiac surgery. These patients were genotyped and a modified genetic risk score (LPA GRS) determining Lp(a) levels was generated. RNAsequencing and vascular superoxide (O2 .-) measurements were performed in internal mammary arteries (IMA), and the contribution of NADPH oxidases and uncoupled endothelial nitric oxide synthase (eNOS) determined. The median follow-up was 5.07 years.
Results: Increased plasma Lp(a) (p=0.03) and LPA GRS (p=0.01), were associated with elevated arterial O2 .- in the overall patient population, an effect that was driven by non-diabetics. This effect was primarily due to eNOS uncoupling via reduced vascular tetrahydrobiopterin bioavailability. There was no significant impact of Lp(a) variability on vascular NADPH oxidase-derived O2 .- (p=0.13). RNA-sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signaling in high Lp(a) patients, although there was no association with systemic biomarkers of inflammation (i.e. hsCRP) (p=0.82) or oxidative stress (i.e. malondialdehyde) (p=0.61). Finally, both LPA GRS (HR[95% CI]=3.615[1.044-12.515], p=0.043) and high plasma Lp(a) (HR[95% CI]=3.286 [1.003-10.767], p=0.049) were associated with elevated risk for cardiac mortality. This association was vascular O2 .--dependent, implying that redox-sensitive inflammatory signaling may be a link between Lp(a) and cardiovascular risk. All above associations were independent from plasma ApoB.
Conclusions: This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.8MB, Terms of use)
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- Publisher copy:
- 10.1161/atvbaha.125.322924
Authors
+ British Heart Foundation
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- Funder identifier:
- https://ror.org/02wdwnk04
- Grant:
- FS/16/15/32047
- RG/F/21/110040
- CH/F/21/90009
- Publisher:
- American Heart Association
- Journal:
- Arteriosclerosis, Thrombosis, and Vascular Biology More from this journal
- Publication date:
- 2025-10-30
- Acceptance date:
- 2025-10-16
- DOI:
- EISSN:
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1524-4636
- ISSN:
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1079-5642
- Language:
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English
- Keywords:
- Pubs id:
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2300643
- Local pid:
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pubs:2300643
- Deposit date:
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2025-10-21
- ARK identifier:
Terms of use
- Copyright holder:
- Polkinghorne et al
- Copyright date:
- 2025
- Rights statement:
- © 2025 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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