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1.
Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review.
Vuong, JT, Stein-Merlob, AF, Nayeri, A, Sallam, T, Neilan, TG, Yang, EH
Journal of the American College of Cardiology. 2022;(6):577-593
Abstract
Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.
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Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis.
Yeo, KP, Lim, HY, Angeli, V
Cells. 2021;(6)
Abstract
In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.
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The Initial Human Atherosclerotic Lesion and Lipoprotein Modification-A Deep Connection.
Torzewski, M
International journal of molecular sciences. 2021;(21)
Abstract
Atherosclerosis research typically focuses on the evolution of intermediate or advanced atherosclerotic lesions rather than on prelesional stages of atherogenesis. Yet these early events may provide decisive leads on the triggers of the pathologic process, before lesions become clinically overt. Thereby, it is mandatory to consider extracellular lipoprotein deposition at this stage as the prerequisite of foam cell formation leading to a remarkable accumulation of LDL (Low Density Lipoproteins). As progression of atherosclerosis displays the characteristic features of a chronic inflammatory process on the one hand and native LDL lacks inflammatory properties on the other hand, the lipoprotein must undergo biochemical modification to become atherogenic. During the last 25 years, evidence was accumulated in support of a different concept on atherogenesis proposing that modification of native LDL occurs through the action of ubiquitous hydrolytic enzymes (enzymatically modified LDL or eLDL) rather than oxidation and contending that the physiological events leading to macrophage uptake and reverse transport of eLDL first occur without inflammation (initiation with reversion). Preventing or reversing initial atherosclerotic lesions would avoid the later stages and therefore prevent clinical manifestations. This concept is in accordance with the response to retention hypothesis directly supporting the strategy of lowering plasma levels of atherogenic lipoproteins as the most successful therapy for atherosclerosis and its sequelae. Apart from but unquestionable closely related to this concept, there are several other hypotheses on atherosclerotic lesion initiation favoring an initiating role of the immune system ('vascular-associated lymphoid tissue' (VALT)), defining foam cell formation as a variant of lysosomal storage disease, relating to the concept of the inflammasome with crystalline cholesterol and/or mitochondrial DAMPs (damage-associated molecular patterns) being mandatory in driving arterial inflammation and, last but not least, pointing to miRNAs (micro RNAs) as pivotal players. However, direct anti-inflammatory therapies may prove successful as adjuvant components but will likely never be used in the absence of strategies to lower plasma levels of atherogenic lipoproteins, the key point of the perception that atherosclerosis is not simply an inevitable result of senescence. In particular, given the importance of chemical modifications for lipoprotein atherogenicity, regulation of the enzymes involved might be a tempting target for pharmacological research.
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4.
Role of lysosomes in physiological activities, diseases, and therapy.
Zhang, Z, Yue, P, Lu, T, Wang, Y, Wei, Y, Wei, X
Journal of hematology & oncology. 2021;(1):79
Abstract
Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.
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Ultrastructural Pathology of Atherosclerosis, Calcific Aortic Valve Disease, and Bioprosthetic Heart Valve Degeneration: Commonalities and Differences.
Kostyunin, A, Mukhamadiyarov, R, Glushkova, T, Bogdanov, L, Shishkova, D, Osyaev, N, Ovcharenko, E, Kutikhin, A
International journal of molecular sciences. 2020;(20)
Abstract
Atherosclerosis, calcific aortic valve disease (CAVD), and bioprosthetic heart valve degeneration (alternatively termed structural valve deterioration, SVD) represent three diseases affecting distinct components of the circulatory system and their substitutes, yet sharing multiple risk factors and commonly leading to the extraskeletal calcification. Whereas the histopathology of the mentioned disorders is well-described, their ultrastructural pathology is largely obscure due to the lack of appropriate investigation techniques. Employing an original method for sample preparation and the electron microscopy visualisation of calcified cardiovascular tissues, here we revisited the ultrastructural features of lipid retention, macrophage infiltration, intraplaque/intraleaflet haemorrhage, and calcification which are common or unique for the indicated types of cardiovascular disease. Atherosclerotic plaques were notable for the massive accumulation of lipids in the extracellular matrix (ECM), abundant macrophage content, and pronounced neovascularisation associated with blood leakage and calcium deposition. In contrast, CAVD and SVD generally did not require vasculo- or angiogenesis to occur, instead relying on fatigue-induced ECM degradation and the concurrent migration of immune cells. Unlike native tissues, bioprosthetic heart valves contained numerous specialised macrophages and were not capable of the regeneration that underscores ECM integrity as a pivotal factor for SVD prevention. While atherosclerosis, CAVD, and SVD show similar pathogenesis patterns, these disorders demonstrate considerable ultrastructural differences.
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6.
Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation.
Marchio, P, Guerra-Ojeda, S, Vila, JM, Aldasoro, M, Victor, VM, Mauricio, MD
Oxidative medicine and cellular longevity. 2019;:8563845
Abstract
Atherosclerosis is a chronic vascular inflammatory disease associated to oxidative stress and endothelial dysfunction. Oxidation of low-density lipoprotein (LDL) cholesterol is one of the key factors for the development of atherosclerosis. Nonoxidized LDL have a low affinity for macrophages, so they are not themselves a risk factor. However, lowering LDL levels is a common clinical practice to reduce oxidation and the risk of major events in patients with cardiovascular diseases (CVD). Atherosclerosis starts with dysfunctional changes in the endothelium induced by disturbed shear stress which can lead to endothelial and platelet activation, adhesion of monocytes on the activated endothelium, and differentiation into proinflammatory macrophages, which increase the uptake of oxidized LDL (oxLDL) and turn into foam cells, exacerbating the inflammatory signalling. The atherosclerotic process is accelerated by a myriad of factors, such as the release of inflammatory chemokines and cytokines, the generation of reactive oxygen species (ROS), growth factors, and the proliferation of vascular smooth muscle cells. Inflammation and immunity are key factors for the development and complications of atherosclerosis, and therefore, the whole atherosclerotic process is a target for diagnosis and treatment. In this review, we focus on early stages of the disease and we address both biomarkers and therapeutic approaches currently available and under research.
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Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection.
McKibben, RA, Margolick, JB, Grinspoon, S, Li, X, Palella, FJ, Kingsley, LA, Witt, MD, George, RT, Jacobson, LP, Budoff, M, et al
The Journal of infectious diseases. 2015;(8):1219-28
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Abstract
BACKGROUND Heightened immune activation among human immunodeficiency virus (HIV)-infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and soluble CD14 (sCD14), and monocyte chemoattractant protein 1 (CCL2) with subclinical atherosclerosis among men with and those without HIV infection in the Multicenter AIDS Cohort Study. METHODS We performed noncontrast computed tomography on 906 men (566 HIV-infected men and 340 HIV-uninfected men), 709 of whom also underwent coronary computed tomographic angiography. Associations between each biomarker and the prevalence of coronary plaque, the prevalence of stenosis of ≥50%, and the extent of plaque were assessed by logistic and linear regression, adjusting for age, race, HIV serostatus, and cardiovascular risk factors. RESULTS Levels of all biomarkers were higher among HIV-infected men, of whom 81% had undetectable HIV RNA, and were associated with lower CD4(+) T-cell counts. In the entire population and among HIV-infected men, higher biomarker levels were associated with a greater prevalence of coronary artery stenosis of ≥50%. Higher sCD163 levels were also associated with greater prevalences of coronary artery calcium, mixed plaque, and calcified plaque; higher CCL2 levels were associated with a greater extent of noncalcified plaque. CONCLUSIONS sCD163, sCD14, and CCL2 levels were elevated in treated HIV-infected men and associated with atherosclerosis. Monocyte activation may increase the risk for cardiovascular disease in individuals with HIV infection.
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Anti-inflammatory therapies for cardiovascular disease.
Ridker, PM, Lüscher, TF
European heart journal. 2014;(27):1782-91
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Abstract
Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1β generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.
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Pathogenic role of modified LDL antibodies and immune complexes in atherosclerosis.
Lopes-Virella, MF, Virella, G
Journal of atherosclerosis and thrombosis. 2013;(10):743-54
Abstract
There is strong evidence supporting a key role of the adaptive immune response in atherosclerosis, given that both activated Th cells producing predominantly interferon-γ and oxidized LDL (oxLDL) and the corresponding antibodies have been isolated from atheromatous plaques. Studies carried out using immune complexes (IC) prepared with human LDL and rabbit antibodies have demonstrated proatherogenic and pro-inflammatory properties, mostly dependent on the engagement of Fcγ receptors Ⅰ and Ⅱ in macrophages and macrophage-like cell lines. Following the development of a methodology for isolating modified LDL (mLDL) antibodies from serum and isolated IC, it was confirmed that antibodies reacting with oxLDL and advanced glycation end product-modified LDL are predominantly IgG of subtypes 1 and 3 and that mLDL IC prepared with human reagents possesses pro-inflammatory and proatherogenic properties. In previous studies, LDL separated from isolated IC has been analyzed for its modifications, and the reactivity of antibodies isolated from the same IC with different LDL modifications has been tested. Recently, we obtained strong evidence suggesting that the effects of mLDL IC on phagocytic cells are modulated by the composition of the mLDL. Clinical studies have shown that the level of mLDL in circulating IC is a strong predictor of cardiovascular disease (CVD) and, in diabetic patients, other significant complications, such as nephropathy and retinopathy. In conclusion, there is convincing ex vivo and clinical data supporting the hypothesis that, in humans, the humoral immune response to mLDL is pathogenic rather than protective.
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How do elevated triglycerides and low HDL-cholesterol affect inflammation and atherothrombosis?
Welty, FK
Current cardiology reports. 2013;(9):400
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Abstract
This review article summarizes recent research into the mechanisms as to how elevated levels of triglyceride (TG) and low levels of high- density- lipoprotein cholesterol (HDL-C) contribute to inflammation and atherosclerosis. Evidence supports the role of TG-rich lipoproteins in signaling mechanisms via apolipoproteins C-III and free fatty acids leading to activation of NFKβ, VCAM-1 and other inflammatory mediators which lead to fatty streak formation and advanced atherosclerosis. Moreover, the cholesterol content in TG-rich lipoproteins has been shown to predict CAD risk better than LDL-C. In addition to reverse cholesterol transport, HDL has many other cardioprotective effects which include regulating immune function. The "functionality" of HDL appears more important than the level of HDL-C. Insulin resistance and central obesity underlie the pathophysiology of elevated TG and low HDL-C in metabolic syndrome and type 2 diabetes. Lifestyle recommendations including exercise and weight loss remain first line therapy in ameliorating insulin resistance and the adverse signaling processes from elevated levels of TG-rich lipoproteins and low HDL-C.