Macrophages: an elusive yet emerging therapeutic target of atherosclerosis (original) (raw)
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The Journal of Lipid Research, 2014
Despite recent advances in our treatment and understanding of its biology, CVD contributes to one in every three deaths (1, 2). Additionally, CVD costs more than any other condition with an estimated annual burden of $312 billion, an astonishing fi gure in light of the growing interest in healthcare utilization and costs (1). This unacceptably high disease burden galvanizes efforts to better understand mechanisms contributing to CVD and developing novel diagnostic and therapeutic strategies. At the epicenter of the most devastating forms of CVD, including myocardial infarction, peripheral vascular disease, and stroke, is atherosclerosis. Atherosclerosis is a chronic condition of the arterial lining characterized by a prolonged asymptomatic phase, making it diffi cult to study in humans. Thus, mouse models have been invaluable in understanding disease mechanisms (3, 4). A hallmark feature of atherosclerosis is the accumulation of cholesterol-loaded macrophages within the vessel wall (5). At the early stages of atherosclerosis, macrophages ingest modifi ed lipoproteins to form "foam cells," and in turn release various substances that recruit smooth muscle cells and other immune cells, ultimately leading to advanced plaque formation (6). Macrophages, as well as other immune cells, have a powerful impact on disease progression (7). Therefore, macrophages are a pivotal cell type in the pathogenesis of atherosclerosis and potential targets for therapy.
BIOMARKERS IDENTIFICATION AND THERAPY TARGET IN MACROPHAGE OF ATHEROSCLEROSIS: SYSTEMATIC REVIEW
Asian Journal of Pharmaceutical and Clinical Research, 2021
Macrophages are known to play an important role in the initiation and progression of atherosclerosis; however, the molecular signaling pathways in macrophages that are responsible for plaque rupture have not been fully identified. This study aims to identify biomarkers and therapy targets in macrophages in atherosclerotic conditions by systematic review. Research procedure of systematic reviews using the PRISMA protocol. The search engine used in this study is PubMed, with the keywords ([macrophage] AND atherosclerosis) AND (signaling pathway OR signaling pathway), the reference application used is Zotero to screen clinical articles. There were 689 articles identified and 11 clinical articles in inclusion criteria were obtained. The identification resulted in 30 biomarkers associated with macrophages in atherosclerotic conditions. The proposed biomarkers of atherosclerosis are interleukin (IL)-1β and IL-18. The proposed potential therapy targets for atherosclerosis are LOX-1 and schematic images of biomarkers in atherosclerotic plaques.
Role of macrophages in atherosclerosis
2020
Atherosclerosis is a chronic inflammatory state, which arise from the imbalance in lipid metabolism. Over the last decade, studies have showing the association of macrophages with this maladaptive immune response. Macrophages differentiated from monocytes and populate at the growing atherosclerotic lesions. At the lesion site by accumulating lipid they actively participate in the formation of atherosclerotic plaque. These plaques are very susceptible to rupture which can lead to myocardial infarction or stroke. In future more studies are needed to classify different macrophage populations according to their phenotypic and functional characteristics to identify their roles in the pathogenesis of atherosclerosis. This review highlights several aspects of macrophages activation, diversity, recruitment, and foam cell formation in atherosclerosis.
Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation
Science Advances, 2015
Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E-deficient mice (Apoe −/− ) with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.
CXCL4-Induced Macrophages: A Novel Therapeutic Target in Human Atherosclerosis?
Atherogenesis, 2012
Atherosclerosis and its consequences (i.e. myocardial infarction and cardiac death) remain the major cause of morbidity and mortality in Western countries (Roger et al. 2011). Despite clinical advances that have substantially improved outcomes in patients suffering from coronary artery disease, including pharmacological interventions (e.g. novel anti platelet therapies, statins, etc.) as well as interventional and surgical therapies (e.g. drug-eluting stents), there is still a huge demand for improved diagnostic tools to identify patients at risk for adverse events as well as therapeutic means to prevent adverse events in these patients. Biomarkers such as high sensitivity CRP (Ridker 2007) or high sensitivity troponin T (Kurz et al. 2011) have brought some improvement in identifying patients requiring more intense treatment; however, the clinical need for better tools remains. An important concept that may help to improve clinical care for patients with coronary artery disease is the inducement of plaque stability. Atherosclerotic lesions can show features of plaque stability or plaque instability (Naghavi et al. 2003a, Naghavi et al. 2003b). Stable plaques are characterized by a thick fibrous cap and a small necrotic core. By contrast, unstable plaques display a thin fibrous cap and a large necrotic core consisting of apoptotic macrophages, foam cells, and smooth muscle cells. Unstable plaques are more likely to rupture, and plaque rupture may subsequently result in thrombosis and occlusion of the vessel leading to a myocardial infarction or stroke. A promising approach to identify potential markers of plaque instability may be the study of atherogenesis on a cellular and molecular level. During the development of atherosclerotic lesions, blood monocytes adhere to the activated endothelium, transmigrate into the subendothelial space, and differentiate towards macrophages, dendritic cells, or foam cells (Galkina & Ley 2009). Among the various leukocyte types involved in atherogenesis, monocytes and monocyte-derived macrophages represent the major fraction. The monocyte-macrophage differentiation process is affected by the extracellular matrix as well as by the combination of chemokines and cytokines representing the micromilieu of the plaque (Shashkin et al. 2005). In addition, cell-cell interactions may also affect the fate of monocytes within the atherosclerotic plaque. Monocyte-derived cells secrete chemokines, cytokines, and other mediators, leading to attraction of other immune cells and thereby promoting plaque progression and plaque instability (Shashkin et al. 2005). While it was initially thought that monocyte-derived macrophages represent a homogenous population www.intechopen.com
Erciyes Medical Journal, 2021
Knowlege of the mechanism of atherosclerosis in chronic and inflammatory diseases is important in health care management. According to the World Health Organization, approximately 17.9 million people die from atherosclerosis annually. Macrophages played a major role in the immune response and pathophysiology of atherosclerosis. This review presents the role of macrophage in the development of atherosclerosis.
Inhibiting Lox-1 Receptor in Macrophages in Atherosclerosis
2020
Cardiovascular disease is the leading cause of death in the United States. During the process of plaque development called atherosclerosis, oxidized low-density lipoproteins (oxLDL) penetrate the endothelial lining of the arterial wall. The damage to the endothelial wall induces a signaling pathway to trigger an inflammatory response. Monocytes then phagocytose oxLDL in an attempt to prevent damage to the endothelial wall and ultimately transform into foam cells that constitute plaque tissue. This study explores the prevention of arterial plaque buildup in atherosclerosis using miRNA let-7g. Through bioinformatics, lectin-type oxidized LDL receptor (LOX-1), a macrophage scavenger receptor protein that uptakes oxLDL, leading to foam cell formation, was identified as a potential target. After a thorough literature review, miRNA let-7g was found to be the most promising miRNA that inhibits LOX-1 expression. By preventing the expression of LOX-1, the macrophage will no longer respond to oxLDL signaling and ultimately inhibit plaque development. Our aim was to determine if LOX-1 expression in macrophages would increase in a dose dependent manner in response to increased oxLDL concentrations. LOX-1 expression in human macrophage primary cell cultures was measured using a flow cytometry assay. We found that oxLDL concentration was not correlated with macrophages' expression of LOX-1 receptor in a dose-dependent manner. This suggests that inflammatory signaling molecules are needed for LOX-1 upregulation and increased oxLDL uptake. It is expected that using let-7g in conjunction with an antiinflammatory compound, such as rapamycin, will further inhibit oxLDL uptake by macrophages and result in a novel treatment for atherosclerosis.
Circulation, 2007
Background-The peroxisome proliferator-activated receptor-␣ (PPAR␣) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPAR␣ ligands have been shown to reduce cardiovascular events in high-risk subjects. PPAR␣ expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. Methods and Results-To examine the contribution of PPAR␣ expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR Ϫ/Ϫ) mice were reconstituted with bone marrow from PPAR␣ Ϫ/Ϫ or PPAR␣ ϩ/ϩ mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPAR␣ Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPAR␣ Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPAR␣ ϩ/ϩ 3 LDLR Ϫ/Ϫ mice. Peritoneal macrophages from PPAR␣ Ϫ/Ϫ mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPAR␣ Ϫ/Ϫ macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-B-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-B gene expression levels in vivo in atherosclerotic lesions of PPAR␣ Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice compared with the lesions of control PPAR␣ ϩ/ϩ 3 LDLR Ϫ/Ϫ mice. Conclusions-These data demonstrate that PPAR␣ expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity. (Circulation. 2007;116:1404-1412.) Key Words: atherosclerosis Ⅲ macrophages Ⅲ proteins Ⅲ receptors P eroxisome proliferator-activated receptor-alpha (PPAR␣) is a ligand-activated transcription factor that plays an important role in lipid metabolism and inflammation. PPAR␣ regulates a number of genes involved in inflammation and the metabolism of cellular lipids, plasma lipoproteins, and glucose. 1,2
Vessel Plus, 2021
Atherosclerosis is the main pathological basis of most cardiovascular diseases and the leading health threat in the world. Of note, lipid-lowering therapy could not completely retard atherosclerosis progression, even in patients that treated with combined statins and PCSK9 inhibitors. This failure further impels researchers to explore other underlying therapeutic strategies except for lipid-lowering. Monocytes and macrophages are the major immune cell groups in atherosclerotic plaques. They play important roles in all stages of atherosclerosis, including the occurrence, advance and regression. It is interesting that macrophages are demonstrated to have plastic and heterogenous characteristics within the dynamic atherosclerotic plaque microenvironment. Furthermore, the phenotype of macrophages can switch upon different microenvironmental stimulus. Therefore, macrophages have become a potential therapeutic target for anti-atherosclerosis treatment. This article reviews the phenotypic diversity of macrophages and their roles in dynamic atherosclerotic plaque microenvironment, especially the related signaling pathways involved in macrophage polarization and compounds exhibited therapeutic effects.