LOX-1: A potential driver of cardiovascular risk in SLE patients

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.

Speckle tracking imaging combined with myocardial comprehensive index to evaluate left ventricular function changes in patients with systemic lupus erythematosus

“…There was a statistically significantly increase in PSD in the mild‐to‐moderate and severe groups compared to the control group, indicating that the dispersion of myocardial mechanical motion is increased, that is, myocardial systolic synchronization is worse 16 . It has been suggested that the deposition of SLE‐associated immune complexes in the cardiovascular system may lead to degeneration of cardiomyocytes and myocardial sympathetic nerves, which directly leads to the damage of the normal function of cardiomyocytes and the dysfunction of nerve fibers in the myocardial layer; this, in turn, has a serious impact on myocardial synchronous movement 17 …”

Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

“…These data indicate that the oxLDL/β2-GPI complex and/or its immune complex may also contribute to the development of vascular complications in SLE through upregulation of NET formation. It is noteworthy that LDNs express higher levels of LOX-1 in patients with SLE compared with the normal subjects [139]. Thus, presumably, LOX-1 may play a pivotal role in eliciting NET formation by stimulating neutrophils with oxLDL.…”

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

“…In addition, LOX-1 expression levels in patients with RA positively correlate with plasma L5% or L5 concentrations and are significantly associated with 10-year ASCVD risk scores [ 56 ]. Another study showed that perturbations in plasma lipid content can activate LOX-1 expression and promote inflammatory responses, suggesting that LOX-1 is a potential driver of ASCVD risk in patients with SLE [ 105 ]. LOX-1 expression can be upregulated by other inflammatory mediators [ 84 ], and the binding of L5 to LOX-1 leads to the feedforward elevation of LOX-1 expression [ 56 ], further promoting subsequent atherogenic and inflammatory responses.…”

“…Given that LOX-1 is a multiligand and multifunctional receptor underlying cardiovascular dysfunction and ASCVD [ 92 , 93 , 94 , 95 , 96 , 105 ], a therapy targeting LOX-1 is promising as a treatment for atherosclerosis and vasculopathy [ 131 ]. MicroRNAs, which are short noncoding RNAs, have been recently identified as immune regulators that post-transcriptionally repress mRNA expression.…”