LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review
Abstract
:1. Introduction
2. Molecular Characteristics of LOX-1
2.1. Polymorphisms, Mutations, and Isotypes of LOX-1
2.1.1. Mutations of LOX-1
- Impact on LOX-1 Functionality: Mutations in the OLR1 gene can alter the receptor’s structure and function. For example, specific mutations may affect the receptor’s ability to bind to ox-LDL, either enhancing or inhibiting this critical interaction. Enhanced binding capacity can lead to increased formation of foam cells, accelerating atherosclerotic plaque development. Conversely, mutations that reduce LOX-1’s affinity for ox-LDL could confer protective effects against atherosclerosis.
- Clinical Relevance of Mutations: Specific mutations in the OLR1 gene have been associated with an increased risk of cardiovascular diseases. For instance, specific polymorphisms linked to the OLR-1 gene have been correlated with higher susceptibility to coronary artery disease and myocardial infarction. Understanding these genetic variations can help identify individuals at higher risk and lead to targeted prevention strategies.
2.1.2. Isoforms of LOX-1
- LOXIN Isoform: An important alternative splicing event within the OLR1 gene leads to the production of an isoform known as LOXIN. This isoform lacks a portion of the C-terminal domain, crucial for the receptor’s ability to bind ox-LDL. LOXIN acts as a dominant-negative regulator of the full-length LOX-1 receptor, potentially reducing ox-LDL uptake and subsequent foam cell formation. This suggests that higher levels of LOXIN relative to full-length LOX-1 could be protective against atherosclerosis;
- Therapeutic Implications of LOXIN: Enhancing the expression of LOXIN or administering it as a therapeutic protein could provide a novel approach to preventing or treating atherosclerosis. By competing with the full-length LOX-1 for binding sites, LOXIN could reduce ox-LDL uptake and the ensuing inflammatory responses in the vascular endothelium.
3. Physiological Functions of LOX-1
4. Pathological Function of LOX-1
4.1. LOX-1 Proinflammatory Inductors
4.1.1. Proinflammatory Cytokines and LOX-1
LOX-1 Function in Atherosclerosis and Related Diseases
- Application of Gene Therapy: Genetic modification to regulate the expression of LOX-1 could be a strategy to control its function in the body and prevent its negative effects on cardiovascular diseases and cancer.
- Diet and lifestyle modulation: Starting a healthy lifestyle and a diet rich in antioxidants could help reduce LOX-1 activation and its impact on cardiovascular health and cancer risk.
- Consumption of anti-inflammatory agents: These agents could have beneficial effects by reducing the activation of LOX-1 and its contribution to diseases such as atherosclerosis and cancer.
4.2. Dyslipidemia as a LOX-1 Inducer
4.3. Expression of LOX-1 and Atherosclerosis
LOX-1: Relationship with Atherosclerosis and Thrombosis
5. LOX-1 as a Biomarker
- Incremental Value of sLOX-1 Over Established Biomarkers
- Early Detection: Cardiac troponins are the gold standard for diagnosing AMI due to their high sensitivity and specificity for myocardial injury. However, troponins may only elevate several hours after the onset of AMI. sLOX-1, by contrast, might rise earlier in the course of endothelial activation and oxidative stress, potentially allowing for quicker diagnosis and intervention.
- Sensitivity to Subclinical Atherosclerosis: Unlike troponins and CK-MB, which increase in response to myocardial damage, sLOX-1 levels reflect endothelial dysfunction and oxidative stress, which are early events in atherosclerosis; this makes sLOX-1 a potentially valuable biomarker for identifying subclinical atherosclerosis and predicting cardiovascular events, even before structural heart damage occurs.
- Prognostic Value: Studies have suggested that elevated levels of sLOX-1 are associated with an increased risk of future cardiovascular events, providing prognostic information beyond the acute setting; this could be particularly useful for risk stratification and long-term management of patients with coronary artery disease.
- Integrating sLOX-1 into Clinical Practice
- Diagnostic Algorithms: Integrating sLOX-1 testing into routine diagnostic algorithms for AMI and stroke could complement current biomarkers, potentially leading to earlier and more accurate risk stratification and therapeutic interventions. For example, an elevated sLOX-1 level in a patient with borderline troponin levels could prompt more aggressive management or further diagnostic testing.
- Feasibility: Integrating sLOX-1 testing is feasible only if rapid, cost-effective, and reliable assays are developed. Current enzyme-linked immunosorbent assay (ELISA) kits for sLOX-1 are primarily used in research settings and must be adapted for routine clinical use.
- Challenges and Opportunities for Implementing LOX-1 as a Routine Biomarker
- Standardization: A significant challenge is the lack of standardized thresholds for sLOX-1 levels across different populations and clinical settings. Establishing these norms would require extensive validation studies.
- Cost and Accessibility: As with any new diagnostic tool, cost-effectiveness studies would be crucial to justify the inclusion of sLOX-1 testing in standardized diagnostic protocols, particularly in resource-limited settings.
- Education and Awareness: To ensure its effective use, clinicians must be educated about the implications of sLOX-1 levels and their integration into clinical decision-making processes.
- Regulatory Approval: Gaining regulatory approval for clinical use involves rigorous testing and validation to meet safety and efficacy standards, which can be time-consuming and costly.
6. Concluding Remarks
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Pathology | Target Molecule | Modelo Used | Outcomes |
---|---|---|---|
Atherogenesis/Atherosclerosis | Lectin-like-ox-LDL receptor-1(LOX-1) | In vitro vascular smooth muscle (SMC) cultures and human coronary artery and aortic samples from WHHL rabbits with atherosclerotic lesions for in vivo studies | Ref. [33] Proinflammatory cytokines and LOX-1—Upregulated LOX-1 is a response to proinflammatory cytokines and PPARgamma can mitigate the proinflammatory effects of these cytokines |
Not applicable (Review) | Not applicable (Review) | Ref. [34] Proinflammatory cytokines and LOX-1—Endothelial dysfunction, macrophage migration, and VSMC proliferation | |
LOX-1 | Watanabe heritable hyperlipidemic (WHHL) rabbits | Ref. [79] Expression of LOX-1 and atherosclerosis—Enhanced expression of LOX-1 produced in endothelial cells of the intimal layer in early atherosclerosis | |
Atherosclerosis | Genes related to cholesterol and lipid metabolism: LOX-1 and gen APOE | Knockout mice (KO) for Apoe and Ldlr genes. Apoe KO mice: Develop hypercholesterolemia and atherosclerotic lesions at an early age. Ldlr KO mice: They have a similar phenotype but are more attenuated | Ref. [85] Expression of LOX-1 and atherosclerosis—The collection of accumulated mutations over the past decades represents a valuable source of animal models for studying human genetic disorders |
LOX-1 | Reviews previous studies investigating the expression of LOX-1 in vascular endothelial cells and macrophages in human atherosclerotic lesions and in animal models (not specified) | Ref. [41] Proinflammatory inductors—Controlling gene expression and targeting specific cells offers hope for developing new treatments to regress atherosclerotic lesions and potentially prevent their formation | |
LOX-1 and ox-LDL (low-density lipoprotein) | Macrophages of LOX-1 knockout mice | Ref. [38] Proinflammatory inductors—Lysophosphatidylcholine and proinflammatory cytokines highly induce the expression of LOX-1, which increases the uptake of ox-LDL by macrophages in atherosclerotic lesions | |
Upregulation of LOX-1 by palmitic acid stimulation | Macrophages THP1 y Raw264.7 | Ref. [39] Proinflammatory inductors—Palmitic acid promotes the expression of LOX-1 in macrophages, contributing to the development of atherosclerosis by increasing ox-LDL uptake | |
LDL | Review of Atherosclerosis. Endothelial cells, leukocytes, and intimal smooth muscle cells | Ref. [86] Proinflammatory inductors— Atherosclerosis is a multifocal immunoinflammatory disease of medium and large arteries involving endothelial cells, leukocytes, and smooth muscle cells | |
Scavenger receptor A and CD36 and LOX-1 | Not applicable (Review) | Ref. [73] Relationship with atherosclerosis and thrombosis—The primary contributors to the accumulation of lipids and inflammatory cells in arterial walls are CD36 and LOX-1, playing a crucial role in plaque genesis and progression | |
LOX-1 | Human coronary artery endothelial cells | Ref. [76] Relationship with atherosclerosis and thrombosis—The interaction between oxidized ox-LDL and angiotensin II increases ox-LDL uptake by coronary artery endothelial cells, leading to enhanced cell injury | |
LOX-1 | Apo-E knockout mice fed with a high-cholesterol diet | Ref. [65] Dyslipidaemia as a LOX-1 inducer— The synergistic inhibitors of LOX-1 (rosuvastatin and candesartan) affected the expression and phosphorylation of MAPK, reducing atherosclerosis by 67% in the murine model | |
Scavenger receptors and Toll-like receptors | Inflammatory and atherosclerotic processes in humans (Review) | Ref. [80] Relationship with atherosclerosis and thrombosis—Atherosclerosis is the cause of heart attacks, strokes, and ischemic gangrene. This condition involves the recruitment of transformed monocytes and the activation of T cells. In later stages, it leads to plaque formation and rupture | |
Components of LDL carrying cholesterol | Mouse models (Review) | Ref. [81] Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in animal models | |
Scavenger receptors and Toll-like receptors | Not applicable (Review) | Ref. [82] Relationship with atherosclerosis and thrombosis—Atherosclerosis begins with the internalization of ox-LDL in the subendothelium, increasing its permeability and the expression of cytokines, chemokines, and adhesion molecules | |
Atherosclerosis | LOX-1 and global DNA methylation. | Apolipoprotein-E-deficient (ApoE−/−) mice treated to induce hyperhomocysteinemia (HHcy) | Ref. [47] Proinflammatory inductors— Homocysteine-induced atherosclerosis is closely associated with induced hypomethylation status in blood vessels and this process is partially mediated by LOX-1 DNA methylation. Homocysteine (Hcy) is an independent risk factor of atherosclerosis but is involvement with the methionine cycle |
Hypertension and atherogenesis | LOX-1 and ox-LDL | Review of studies of cultures of vascular endothelial cells and animal models of atherosclerosis and hyperlipidemia, such as WHHL rabbits and SHR rats, cholesterol-fed mice, and monkeys | Ref. [55] Expression of LOX-1 and atherosclerosis—Ang II functions to enhance ox-LDL uptake, amplifying cell injury through the overexpression of LOX-1 in the endothelium |
Endothelial dysfunction and atherogenesis | LOX-1 Membrane type 1 MMP (MT1-MMP) Integral role in RhoA and Rac1-dependent signaling pathways (ox-LDL) | In human aortic endothelial cells (HAECs) in culture and in Watanabe rabbits with heritable hyperlipidemia. Fluorescent immunostaining and immunoprecipitation to analyze the colocalization and complex formation between lectin-like-ox-LDL receptor-1(LOX-1) and MT1-MMP in HAECs | Ref. [87] Expression of LOX-1 and atherosclerosis—The main focus of the LOX-1-MT1-MMP axis in the activation pathways of RhoA and Rac1 in response to ox-LDL is highlighted, positioning LOX-1 as a potential therapeutic target for endothelial dysfunction |
Atherosclerosis and endothelial dysfunction | LOX-1, NLRP3 inflammasome, and DNase II. | THP-1 macrophages, human monocytic cell line, and primary peritoneal macrophages from C57BL/6 mice | Ref. [35] Pathological function of LOX-1- LOX-1 and mitochondrial DNA damage drive cardiovascular diseases like atherosclerosis. In macrophages, whereby LOX-1 induces ROS, autophagy, and NLRP3 inflammasome, are crucial in inflammation |
LOX-1 | Human aortic endothelial cells (HAECs) are used and in vitro experiments are performed to study the effect of CRP on the expression of LECTIN-LIKE OX-LDL RECEPTOR-1 (LOX-1), the adhesion of monocytes to endothelial cells, and the uptake of ox-LDL by endothelial cells | Ref. [40] Proinflammatory inductors—C-reactive protein is an inflammatory marker that predicts cardiovascular events, promotes endothelial dysfunction, and increases the expression of endothelial LOX-1 | |
Coronary heart disease and Atherosclerosis | LDL An oxidative modification The acetyl LDL or scavenger receptor | Review of intervention studies using probucol as an antioxidant in the LDL receptor-deficient animal model for atherosclerosis (WHHL rabbit) | Ref. [42] Proinflammatory inductors— Hypercholesterolemia is one of the factors triggering coronary artery disease due to its significance. It is important to note that this disease is multifactorial |
Atherosclerosis, cardiovascular disease | High-density lipoprotein (HDL). | Human endothelial cells to evaluate the ability of 15-LO-modified HDL3 to inhibit the expression of TNF-α-mediated MCP-1 and adhesion molecules. In addition, assays were performed to evaluate the adhesion of monocytes to endothelial cells exposed to HDL3 modified by 15-LO. The pathways responsible for the effects induced by 15-LO-modified HDL3 were investigated, focusing mainly on the activation of NF-κB and AP-1 | Ref. [43] Proinflammatory inductors—Endothelial dysfunction, one of the earliest events in vascular atherogenesis, is exacerbated by the enzymatic modification of HDL3 by 15-LO, resulting in a dysfunctional lipoprotein with proinflammatory characteristics |
Atherosclerosis accelerated by diabetes mellitus | LDL glycosylated | Normal human fibroblasts. The LDL glycosylated in vitro in a slow non-enzymatic reaction obtained from plasma from normolipidemic subjects | Ref. [37] Proinflammatory inductors—Glycosylation of LDL significantly impairs its cellular interactions, including uptake and degradation by fibroblasts, and its ability to stimulate cholesteryl ester synthesis, which may contribute to accelerated atherosclerosis in diabetic patients |
Atherosclerosis and cardiovascular disease (ACVD) | “Find-Me” signals (such as lysophosphatidylcholine), “Eat-Me” signals (such as phosphatidylserine, Mer tyrosine kinase receptor (MerTK), and milk fat globule-EGF factor 8), and “Don’t Eat-Me” signals (such as cluster of differentiation 47 (CD47)). | Studies on atherosclerotic plaques and specialized cells like macrophages and dendritic cells, as well as non-specialized cells with phagocytic capability like endothelial cells and smooth muscle cells. Additionally, the use of Watanabe heritable hyperlipidaemic rabbits (WHHL) as an animal model (Review) | Ref. [60] Dyslipidaemia as a lox-1 inducer—the impaired process of efferocytosis involving various cell types and signalling molecules contributes significantly to the progression of atherosclerosis, highlighting its potential as a target for personalized treatment of cardiovascular disease |
Endothelial dysfunction | LOX-1 | Review in microvascular endothelial cells (HMEC-1) | Ref. [48] Proinflammatory inductors—LOX-1 acts as a mediator of endothelial dysfunction and, in turn, as a promoter of ROS generation, suggesting the involvement of signaling pathways such as mitogen-activated protein kinases (MAPKs) |
LOX-1 | Review of studies in vitro and in animal models (rats and human coronary artery endothelial cells) | Ref. [88] Expression of LOX-1 and atherosclerosis- LOX-1 contributes to endothelial dysfunction by inducing functional changes in these cells, impacting vascular homeostasis. It triggers ROS generation and reduces NO release | |
Coronary heart disease | Not specific (Review) | Mouse models with diabetes-accelerated atherosclerosis | Ref. [78] Expression of LOX-1 and atherosclerosis— The review mentions that the mouse models currently used to study diabetic atherosclerosis must meet the following criteria: persistent diabetes, acceleration of atherosclerosis, and resistance to medical intervention, the most common of which are classified according to the type of diabetes |
Diabetic atherosclerosis | Advanced glycation endproducts–BSA induced LOX-1 expression). VLDL/LDL prominently increased LOX-1 | Streptozotocin-induced diabetic rats(aorta) Cultured aortic endothelial cells stimulated by diabetic rat serum | Ref. [46] Proinflammatory inductors—The serum of diabetic rats shows an accumulation of LOX-1 ligand activity, mainly in the VLDL/LDL fractions |
ox-LDL | Human monocyte-derived macrophage (MDM) The ox-LDL, hyperglycemia, glycoxidation, lipoxidation, increased oxidative stress, and activation of protein kinase C (PKC) | Ref. [77] Proinflammatory cytokines and LOX-1—The most important findings are the glucose-dependent positive regulation of LOX-1 expression and its association with atherosclerosis progression. High glucose involves several signalling pathways, including protein kinase C, mitogen-activated protein kinases, nuclear factor κB, and activated protein-1. The role of oxidative stress is directly related to foam cell formation promoted by high glucose. In summary, hyperglycemia contributes to the development of atherosclerosis in type 2 diabetes | |
Cardiovascular disease | Guanosine triphosphatase small Rho and its target Rho-kinase | Not applicable (Review) | Ref. [89] Pathological function of LOX-1—The activation of the Rho/Rho-kinase signaling pathway plays a crucial role in regulating blood pressure and vasoconstriction, with significant implications in cardiovascular diseases such as hypertension and atherosclerosis. |
Endothelial dysfunction | Rac1 (a member of the GTPase family of the Rho family) | Not applicable (Review) | Ref. [44] The pathological function of LOX-1—The main role of Rac1 as a regulator of multiple cellular signalling pathways affecting cytoskeleton organization, transcription, and cell proliferation, which have implications in endothelial dysfunction and associated pathological conditions such as tumorigenesis, neurodegenerative disorders, liver cirrhosis, and cardiovascular remodeling/hypertension, has been investigated |
LOX-1 and Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3). | A cellular model of endothelial progenitor cel (EPCs) treated with different concentrations of astragaloside IV (ASV) and ox-LDL as a stimulus for cellular dysfunction | Ref. [51] Proinflammatory inductors—Astragaloside IV (ASV) demonstrates protective effects against oxidized low-density lipoprotein (ox-LDL)-induced dysfunction in endothelial progenitor cells (EPCs) through modulation of the LOX-1/NLRP3 pathway, highlighting its potential therapeutic role in diabetic vascular complications | |
LOX-1 and Nod-like receptor nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3). | This is a cellular model of endothelial progenitor cells (EPCs) treated with different concentrations of astragaloside IV (ASV) and ox-LDL as a stimulus for cellular dysfunction | Ref. [51] Proinflammatory inductors—Astragaloside IV (ASV) demonstrates protective effects against oxidized low-density lipoprotein (ox-LDL)-induced dysfunction in endothelial progenitor cells (EPCs) through modulation of the LOX-1/NLRP3 pathway, highlighting its potential therapeutic role in diabetic vascular complications | |
Hypertension | LOX-1 | Spontaneous hypertensive rats (SHR-SP)—Wistar Kyoto Rats (WKY), Dahl salt-sensitive (DS), and salt-resistant rats (DR) | Ref. [36] The pathological function of LOX-1—The increased expression of the endothelial receptor for oxidized LDL (LOX-1) in hypertensive rats suggests the involvement of LOX-1 in endothelium-dependent vasodilation dysfunction |
No specific | Spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY) control | Ref. [90] Proinflammatory inductors—The research on LOX-1 expression in spontaneously hypertensive rats (SHR) offers an invaluable opportunity to better understand the relationship between hypertension and endothelial dysfunction, opening new perspectives in cardiovascular disease pathogenesis research | |
LOX-1 | A molecular–cellular interaction model was reviewed to study the relationship between LDL oxidation ox-LDL, LOX-1, angiotensin II (Ang II), and Ang II receptor type 1 (AT1R) in the pathogenesis of hypertension | Ref. [45] Proinflammatory inductors—Hypertension is associated with vascular oxidative stress, which promotes proliferation and hypertrophy of vascular smooth muscle cells, collagen deposition, endothelial dysfunction, altered vasoconstriction, increased levels of ox-LDL, and changes in the renin–angiotensin system and angiotensin II levels | |
Aortic aneurysm (AA) | Peptide p210 related to apoB-100. | Apolipoprotein E-deficient (ApoE−/−) mice were treated with a vaccine utilizing peptide p210 and then implanted with a pump releasing angiotensin II (Ang II) to induce AA | Ref. [72] Expression of lox-1 and atherosclerosis— The role of apoB-containing lipoproteins in atherosclerosis was studied and suggests a potential connection with protection against abdominal aortic aneurysm through an apoB-related vaccine in mice |
Not specified | LOX-1 | Atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant C3H/HeJ mice fed an atherogenic high-fat diet. (Murine macrosialin) MS does not function as an ox-LDL receptor | Ref. [74] Expression of lox-1 and atherosclerosis—The study shows that MS does not act as a receptor for ox-LDL on the cell surface, even though its expression increases in response to a high-fat diet and oxLDL treatment |
Chronic Venous Disease (CVD) | No specific | An observational study was conducted on 902 women from the general population, aged 45 to 54 years Evaluation of cardiovascular risk factors (ankle/brachial systolic blood pressure index (ABI) and carotid intima-media thickness of the common carotid arteries measured by ultrasound) | Ref. [83] Relationship with atherosclerosis and thrombosis—Soluble LOX-1 levels are elevated in acute myocardial infarction, suggesting a role for the more electronegative fraction (L5) of LDL, which is associated with promoting atherogenesis and thrombus formation |
Coronary Thrombosis | LOX-1 | This is an observational study that analyzed aspirated coronary thrombi from patients with STEMI and without ST-segment elevation myocardial infarction (NSTEMI) to evaluate the expression of LECTIN-LIKE OX-LDL RECEPTOR-1 (LOX-1) and the relationship between sLECTIN-LIKE OX-LDL RECEPTOR-1 (LOX-1) and L5 levels in peripheral blood | Ref. [84] Relationship with atherosclerosis and thrombosis—sLOX-1 levels are elevated in acute myocardial infarction (AMI), particularly in ST-segment-elevation myocardial infarction (STEMI), suggesting a potential role for L5 in triggering atherogenesis and promoting thrombi formation |
Hypercholesterolemia | LOX-1 | Wistar rats were divided into groups; some were fed a high-cholesterol diet and others were treated with Aegeline/atorvastatin along with the same diet. | Ref. [66] Dyslipidemia as a LOX-1 inducer— Aegeline (AG) is shown to be an effective anti-hypercholesterolemic agent by reducing Ox-LDL and LOX-1 levels, suggesting its potential as a novel diagnostic strategy for hypercholesterolemia and vascular diseases |
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Sánchez-León, M.E.; Loaeza-Reyes, K.J.; Matias-Cervantes, C.A.; Mayoral-Andrade, G.; Pérez-Campos, E.L.; Pérez-Campos-Mayoral, L.; Hernández-Huerta, M.T.; Zenteno, E.; Pérez-Cervera, Y.; Pina-Canseco, S. LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review. Int. J. Mol. Sci. 2024, 25, 5276. https://doi.org/10.3390/ijms25105276
Sánchez-León ME, Loaeza-Reyes KJ, Matias-Cervantes CA, Mayoral-Andrade G, Pérez-Campos EL, Pérez-Campos-Mayoral L, Hernández-Huerta MT, Zenteno E, Pérez-Cervera Y, Pina-Canseco S. LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review. International Journal of Molecular Sciences. 2024; 25(10):5276. https://doi.org/10.3390/ijms25105276
Chicago/Turabian StyleSánchez-León, Maria Eugenia, Karen Julissa Loaeza-Reyes, Carlos Alberto Matias-Cervantes, Gabriel Mayoral-Andrade, Eduardo L. Pérez-Campos, Laura Pérez-Campos-Mayoral, María Teresa Hernández-Huerta, Edgar Zenteno, Yobana Pérez-Cervera, and Socorro Pina-Canseco. 2024. "LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review" International Journal of Molecular Sciences 25, no. 10: 5276. https://doi.org/10.3390/ijms25105276