AUTHOR=Ashok Karthik , Martinez Tyra , Sesen Julie , Nasim Sana , Lang Shih-Shan , Heuer Gregory , Tucker Alexander , Lopez-Ramirez Miguel Alejandro , Smith Edward R. , Ghalali Aram 

TITLE=Lectin-type oxidized LDL receptor-1 as a potential therapeutic target for cerebral cavernous malformations treatment

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 18 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1442110

DOI=10.3389/fnins.2024.1442110

ISSN=1662-453X

ABSTRACT=Introduction: Cerebral cavernous malformations (CCMs) are pathologic lesions comprised of clusters of thin-walled capillaries characterized by abnormal proliferation, angiogenesis, and bleeding secondary to somatic or germline mutations in endothelial cells. CCMs can cause headache, seizure or neurological deficits, and there is a clinical need to develop better tools to detect and follow their progression that might complement the current use of expensive neuroimaging techniques. Here we present data supporting the utility of LOX-1 (lectin-type oxidized LDL receptor 1), a 50kDa transmembrane protein implicated in endothelial cell dysfunction and ischemia, as a target for CCM. 

Methods: CCM urine samples (n=23) were collected from pediatric patients. Matched healthy controls (n=24) were collected from pediatric patients with either Chiari I malformation or fatty filum, and otherwise normal findings. All samples were collected with patient/family consent and institutional review board approval.
Samples were analyzed with Olink Proteomic Proximity Extension assay (PEA). Differences in expression for 2,925 unique proteins were quantified between control samples and CCM urine samples. The results were normalized, validated, and analyzed for demographic bias. In addition to urine samples, CCM tissue from patients was harvested and used to create primary cell lines for in vitro analysis of LOX-1 expression, in addition to immunofluorescence of lesional tissue excised at surgery.

Results: ANOVA analysis of the CCM urine samples showed a statistically significant increase in LOX-1 compared to the controls, with CCM patients exhibiting a >5-fold increase in urinary expression. Corroborating these elevated levels of circulating marker, analysis of source tissue from surgically resected CCMs revealed that LOX-1 is increased in both CCM patient cavernoma primary cell lines and operative specimens. 

Conclusions: LOX-1 is involved with pathways implicated in CCM pathogenesis and our data here reveals that LOX-1 expression is significantly elevated in CCM patients as compared to healthy control individuals, including both source tissue from surgically excised CCMs and in analysis of samples collected from outside of the central nervous system, particularly urine. This proof-of-principle data suggests that LOX-1 may have potential utility as a target for CCM treatment and supports further investigation related to its potential mechanistic impact on CCM pathogenesis.