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LOX-1: A potential driver of cardiovascular risk in SLE patients
Divya Sagar1, Ranjitha Gaddipati2, Emily L Ongstad2
1Respiratory, Inflammation and Autoimmune, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States of America.
Insights
Systemic lupus erythematosus (SLE) patients show increased soluble LOX-1 (sLOX-1) levels, linked to higher cardiovascular disease (CVD) risk. Targeting LOX-1 may reduce atherosclerosis in SLE patients.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Rheumatology
Background:
- Traditional cardiovascular disease (CVD) risk factors inadequately explain the elevated CVD burden in systemic lupus erythematosus (SLE).
- The oxidized-low-density lipoprotein receptor (LOX-1) is implicated in atherosclerosis and may play a role in SLE-associated CVD.
- Elevated soluble LOX-1 (sLOX-1) levels are observed in SLE patients.
Purpose of the Study:
- To investigate the role of LOX-1 in the pathogenesis of CVD in SLE patients.
- To determine the association between sLOX-1 levels and clinical/biochemical parameters in SLE.
- To explore the cellular mechanisms by which LOX-1 activation contributes to inflammation and vascular injury in SLE.
Main Methods:
- Quantification of sLOX-1 levels in SLE patients.
- Association analysis of sLOX-1 with CVD risk factors, disease activity, and inflammatory markers.
- Flow cytometry to assess LOX-1 expression on immune cells.
- In vitro experiments stimulating patient-derived cells with oxidized-LDL (oxLDL) and immune complexes.
Main Results:
- SLE patients exhibited increased sLOX-1 levels, correlated with proinflammatory HDL, oxLDL, and hsCRP.
- Higher sLOX-1 levels were associated with early disease onset, low disease activity, elevated IL-8, and normal complement/hematological measures.
- LOX-1 expression increased on monocytes and low-density granulocytes; activation led to sLOX-1 release, cytokine production, and neutrophil extracellular trap formation.
Conclusions:
- Lipid alterations in SLE activate LOX-1, promoting inflammatory responses and potentially contributing to atherosclerosis.
- Increased sLOX-1 may serve as a biomarker for heightened CVD risk in SLE.
- LOX-1 blockade presents a potential therapeutic strategy for managing atherosclerosis in SLE.
Abstract:
Traditional cardiovascular disease (CVD) risk factors, such as hypertension, dyslipidemia and diabetes do not explain the increased CVD burden in systemic lupus erythematosus (SLE). The oxidized-LDL receptor, LOX-1, is an inflammation-induced receptor implicated in atherosclerotic plaque formation in acute coronary syndrome, and here we evaluated its role in SLE-associated CVD. SLE patients have increased sLOX-1 levels which were associated with elevated proinflammatory HDL, oxLDL and hsCRP. Interestingly, increased sLOX-1 levels were associated with patients with early disease onset, low disease activity, increased IL-8, and normal complement and hematological measures. LOX-1 was increased on patient-derived monocytes and low-density granulocytes, and activation with oxLDL and immune-complexes increased membrane LOX-1, TACE activity, sLOX-1 release, proinflammatory cytokine production by monocytes, and triggered the formation of neutrophil extracellular traps which can promote vascular injury. In conclusion, perturbations in the lipid content in SLE patients' blood activate LOX-1 and promote inflammatory responses. Increased sLOX-1 levels may be an indicator of high CVD risk, and blockade of LOX-1 may provide a therapeutic opportunity for ameliorating atherosclerosis in SLE patients.
