Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1): A Potential Therapeutic Target in Ischemic Stroke

Translational Stroke Research https://doi.org/10.1007/s12975-024-01307-z REVIEW Lectin‑Like Oxidized Low‑Density Lipoprotein Receptor‑1 (LOX‑1): A Potential Therapeutic Target in Ischemic Stroke Yue Hu1 · Yuhao Li2 · Yumin Luo1,2,3 · Ningqun Wang1 · Yangmin Zheng1,2 Received: 16 April 2024 / Revised: 22 October 2024 / Accepted: 5 November 2024 © The Author(s) 2024 Abstract Stroke, the leading cause of disability and the second leading cause of death worldwide, is characterized by high morbidity and disability. The lectin-like oxidized low-density lipoprotein receptor (LOX-1) is a scavenger receptor that promotes endothelial dysfunction by recognizing and internalizing oxidized low-density lipoproteins (ox-LDL) to induce the formation, development, and instability of atherosclerotic plaques, ultimately leading to vascular thrombosis. Previous clinical and epidemiological studies have indicated that LOX-1 plays a vital role in cerebral ischemic injury following ischemic stroke. Multiple clinical studies have shown that the genetic polymorphisms in LOX-1 are associated with susceptibility to ischemic stroke. Soluble LOX-1 (sLOX-1), a biomarker of ischemic stroke, is associated with the prognosis of ischemic stroke. This article discusses the clinical and experimental findings on LOX-1 in ischemic stroke and the development of new therapeutic strategies targeting LOX-1. Keywords LOX-1 · Cerebral ischemia · Stroke · sLOX-1 Introduction Stroke is the second leading cause of death in individuals over 60 years of age worldwide, and also the primary cause of permanent disability. Stroke is characterized by high incidence, disability, mortality, and recurrence rates [1]. The occurrence and development of ischemic stroke are complex and its pathogenesis remains unclear. Currently, the only effective reperfusion treatment in the acute phase is a shorttime window, and most patients cannot receive this treatment. Therefore, elucidating the molecular mechanisms of neuronal damage in stroke and identifying novel biomarkers * Yumin Luo * Ningqun Wang * Yangmin Zheng 1 Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China 2 Beijing Geriatric Medical Research Center, Beijing, China 3 Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China and molecular targets for intervention will provide new neuroprotective strategies to address the bottleneck of stroke treatment [2]. Lectin-like oxidized low-density lipoprotein receptor (LOX-1) is a 50 KD type II integrin membrane glycoprotein receptor and a C-type lectin-like receptor family member. Its lectin-like domain contains a basic skeleton of arginine residues, which preferentially binding to negatively charged molecules, including oxidized low-density lipoprotein(oxLDL) [3]. The expression of LOX-1 is generally low under normal physiological conditions. However, LOX-1 is an acute-phase reactant that rapidly increases in expression under the stimuli of various pro-oxidative and pro-inflammation factors, thereby playing an essential role in cell damage induced by oxidative stress and inflammation [4]. LOX-1 mediates the inflammatory activities of endothelial cells and increases the expression of inflammatory chemokines MCP-1 and IL-8 and adhesion molecules P-selectin, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular cell adhesion molecule1(ICAM-1) in endothelial cells, thereby damaging the blood–brain barrier (BBB) and participating in the occurrence of ischemic nerve injury [5, 6]. As a scavenger receptor, LOX-1 participates in the activation, aggregation, and transformation to foam cells of macrophages through the Vol.:(0123456789) Translational Stroke Research binding and internalization of ox-LDL, mediates the release of matrix metalloproteinases (MMP), and promotes the decomposition of collagen fibers in atherosclerotic plaques, leading to plaque rupture, vascular thrombosis, subsequently ischemic stroke, and other complications [7–9]. However, these studies have mainly focused on vascular endothelial injury and atherosclerotic plaque rupture, which indirectly cause nerve injury. In the other hand, previous studies have shown that LOX-1 is upregulated in the brain tissues of animal models of cerebral ischemia, exacerbating cerebral infarction and neurological dysfunction, increasing BBB leakage, and promoting the release of inflammatory mediators and chemokines [10–12]. LOX-1 gene polymorphism is associated with susceptibility to ischemic stroke [13, 14]. The hydrolytic form of LOX-1, soluble LOX-1 (sLOX-1), is elevated in the plasma of patients with ischemic stroke and is associated with the prognosis of stroke [15]. However, there remains a gap in the literature regarding the effects and mechanisms of action of LOX-1 in neuronal damage after cerebral ischemia. With increasing evidence supporting the important role of LOX-1 in brain injury following ischemic stroke, LOX-1 Fig. 1  Structure and selective splicing of human OLR1 gene has become a novel biomarker and target for intervention in ischemic stroke, providing new therapeutic strategies for the neuroprotective treatment of ischemic stroke. However, the targeting of LOX-1 as a neuroprotective strategy requires further investigation. This review discusses the structure, expression regulation, and clinical and experimental findings on LOX-1 in ischemic stroke as well as the development of new therapeutic strategies targeting LOX-1. Structure of LOX‑1 LOX-1 is encoded by the OLR1 gene in the p12-13.5 region of chromosome 12 [16]. The OLR1 gene has a total length of approximately 7000 bp and contains six exons and five introns. These six exons undergo selective splicing to form three different splicing variants, as shown in Fig. 1. The first variant NM_002543 contains the entire OLR1 gene with all six exons and exhibits complete ox-LDL binding activity after transcription. The encoded LOX-1 protein is a 50 kDa type II transmembrane protein that contains 273 amino acid residues and is a homodimer. LOX-1 is a member of Translational Stroke Research the C-type lectin-like family, consisting of four structural domains: C-type lectin-like domain (CTLD), encoded by exon 4–6; single transmembrane domain, encoded by exon 2; NECK domain containing α-spiral coil, encoded by exon 3; short N-terminal cytoplasmic domain encoded by exon 1 and exon 2 [17]. The C-type lectin-like folding of LOX-1 in mammals is highly conserved, with six cysteine residues supporting lectin-like folding by forming three intramolecular disulfide bonds. The electrostatic interaction between the alkaline residues in the lectin-like domain and the negatively charged ox-LDL is crucial for the binding of ox-LDL and LOX-1 [18]. The second variant, NM_001172632, lacks exon 4 and is the shortest spliceosome, with a total length of 950 bp. NM_001172632 is shorter than LOX-1 af (...truncated)