LOX-1 in atherosclerosis: biological functions and pharmacological modifiers
TL;DR: This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOx-1 by vasculoprotective drugs, and the importance of LOZ-1 in the pathogenesis of atherosclerosis to suggest an attractive therapeutic target for the treatment of human atherosclerotic diseases.
Abstract: Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.
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TL;DR: This Review highlights recent insights into the structural features that determine the function of scavenger receptors and the emerging role that these receptors have in immune responses, notably in macrophage polarization and in the pathogenesis of diseases such as atherosclerosis and Alzheimer's disease.
Abstract: Scavenger receptors were originally identified by their ability to recognize and to remove modified lipoproteins; however, it is now appreciated that they carry out a striking range of functions, including pathogen clearance, lipid transport, the transport of cargo within the cell and even functioning as taste receptors. The large repertoire of ligands recognized by scavenger receptors and their broad range of functions are not only due to the wide range of receptors that constitute this family but also to their ability to partner with various co-receptors. The ability of individual scavenger receptors to associate with different co-receptors makes their responsiveness extremely versatile. This Review highlights recent insights into the structural features that determine the function of scavenger receptors and the emerging role that these receptors have in immune responses, notably in macrophage polarization and in the pathogenesis of diseases such as atherosclerosis and Alzheimer's disease.
673 citations
TL;DR: The role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and potential anti-Oxidant therapeutic strategies relevant to Atherosclerosis are discussed.
Abstract: Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti-oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis. There is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development. Research over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis.
587 citations
TL;DR: The key contribution of LOx-1 to the atherogenic process has been confirmed in animal models; LOX-1 knockout mice exhibit reduced intima thickness and inflammation and increased expression of protective factors; on the contrary, LOX1 overexpressing mice present an accelerated atherosclerotic lesion formation which is associated with increased inflammation.
Abstract: Oxidized low-density lipoprotein (OxLDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation. Vascular wall cells express on their surface several scavenger receptors that mediate the cellular effects of OxLDL. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the main OxLDL receptor of endothelial cells, and it is expressed also in macrophages and smooth muscle cells. LOX-1 is almost undetectable under physiological conditions, but it is upregulated following the exposure to several proinflammatory and proatherogenic stimuli and can be detected in animal and human atherosclerotic lesions. The key contribution of LOX-1 to the atherogenic process has been confirmed in animal models; LOX-1 knockout mice exhibit reduced intima thickness and inflammation and increased expression of protective factors; on the contrary, LOX-1 overexpressing mice present an accelerated atherosclerotic lesion formation which is associated with increased inflammation. In humans, LOX-1 gene polymorphisms were associated with increased susceptibility to myocardial infarction. Inhibition of the LOX-1 receptor with chemicals or antisense nucleotides is currently being investigated and represents an emerging approach for controlling OxLDL-LOX-1 mediated proatherogenic effects.
563 citations
Cites background from "LOX-1 in atherosclerosis: biologica..."
...Basal cellular LOX-1 expression is very low, but it can be induced by several proinflammatory and proatherogenic stimuli [7, 8]....
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...In vivo, the expression of LOX-1 is upregulated in the presence of pathological conditions including atherosclerosis, hypertension, and diabetes [8] (Figure 2)....
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...Nuclear factor kappa B (NF-κB), which is activated by several proinflammatory cytokines,modulates the expression of proinflammatory genes, including adhesion molecules, cytokines, and chemokines, and is also involved in LOX1 upregulation [8, 22]....
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...LOX-1 expression in macrophages can be upregulated by several stimuli, including OxLDL, LPC, high-glucose levels, and proinflammatory cytokines [8]....
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...generated in a local environmentwithin the arterial wall or by other atherogenic stimuli including OxLDL [8]....
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TL;DR: This review aims at giving an introduction into oxidative stress in CVD, with special focus on endothelial dysfunction, and then examining in detail the role of oxidative Stress in the most prevalent of these diseases.
Abstract: Cardiovascular diseases (CVD) are complex entities with heterogenous pathophysiologic mechanisms and increased oxidative stress has been viewed as one of the potential common etiologies. A fine balance between the presence of reactive oxygen species (ROS) and antioxidants is essential for the proper normal functioning of the cell. A basal concentration of ROS is indispensable for the manifestation of cellular functions, whereas excessive levels of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, eventually leading to necrosis and apoptotic cell death. CVD is the main cause of death worldwide with several conditions being affected by oxidative stress. Increased ROS lead to decreased nitric oxide availability and vasoconstriction, promoting arterial hypertension. ROS also negatively influence myocardial calcium handling, causing arrhythmia, and augment cardiac remodeling by inducing hypertrophic signaling and apoptosis. Finally, ROS have also been shown to promote atherosclerotic plaque formation. This review aims at giving an introduction into oxidative stress in CVD, with special focus on endothelial dysfunction, and then examining in detail the role of oxidative stress in the most prevalent of these diseases. Finally, potential nutraceuticals and diets that might be beneficial in diminishing the burden of oxidative stress in CVD are presented.
379 citations
Cites background from "LOX-1 in atherosclerosis: biologica..."
...Some of these responses include endothelial dysfunction, phagocytosis of senescent apoptotic cells, vascular inflammation, foam cell formation, collagen deposition, and adipocyte cholesterol metabolism [48]....
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TL;DR: A systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen and their bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery.
Abstract: Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics.
248 citations
References
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TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.
Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .
19,881 citations
6,754 citations
"LOX-1 in atherosclerosis: biologica..." refers background in this paper
...Daniel Steinberg [6], oxidized LDL (oxLDL) received intense interest as it promotes key steps involved in plaque formation and destabilization....
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...After the milestone study by Dr. Daniel Steinberg [6], oxidized LDL (oxLDL) received intense interest as it promotes key steps involved in plaque formation and destabilization....
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6,184 citations
TL;DR: No significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal - medial thickness of human arteries in vivo.
Abstract: A study in vitro of specimens of human aortic and common carotid arteries was carried out to determine the feasibility of direct measurement (i.e., not from residual lumen) of arterial wall thickness with B mode real-time imaging. Measurements in vivo by the same technique were also obtained from common carotid arteries of 10 young normal male subjects. Aortic samples were classified as class A (relatively normal) or class B (with one or more atherosclerotic plaques). In all class A and 85% of class B arterial samples a characteristic B mode image composed of two parallel echogenic lines separated by a hypoechoic space was found. The distance between the two lines (B mode image of intimal + medial thickness) was measured and correlated with the thickness of different combinations of tunicae evaluated by gross and microscopic examination. On the basis of these findings and the results of dissection experiments on the intima and adventitia we concluded that results of B mode imaging of intimal + medial thickness did not differ significantly from the intimal + medial thickness measured on pathologic examination. With respect to the accuracy of measurements obtained by B mode imaging as compared with pathologic findings, we found an error of less than 20% for measurements in 77% of normal and pathologic aortic walls. In addition, no significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal + medial thickness of human arteries in vivo.
2,475 citations
TL;DR: The molecular cloning, using expression cloning strategy, of an Ox-LDL receptor from vascular endothelial cells is reported, which is a membrane protein that belongs structurally to the C-type lectin family, and is expressed in vivo in vascular endothelium and vascular-rich organs.
Abstract: Endothelial dysfunction or activation elicited by oxidatively modified low-density lipoprotein (Ox-LDL) has been implicated in the pathogenesis of atherosclerosis1–4, characterized by intimal thickening and lipid deposition in the arteries. Ox-LDL and its lipid constituents impair endothelial production of nitric oxide, and induce the endothelial expression of leukocyte adhesion molecules and smooth-muscle growth factors, which may be involved in atherogenesis5–7. Vascular endothelial cells in culture8,9 and in vivo10,11 internalize and degrade Ox-LDL through a putative receptor-mediated pathway that does not involve macrophage scavenger receptors12–15. Here we report the molecular cloning, using expression cloning strategy, of an Ox-LDL receptor from vascular endothelial cells. The cloned receptor is a membrane protein that belongs structurally to the C-type lectin family, and is expressed in vivo in vascular endothelium and vascular-rich organs.
1,309 citations
"LOX-1 in atherosclerosis: biologica..." refers background in this paper
...Lectin-like oxLDL receptor-1 is the major receptor for oxLDL uptake by EC [8]....
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