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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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2.
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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3.
Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis.
Salnikova, D, Orekhova, V, Grechko, A, Starodubova, A, Bezsonov, E, Popkova, T, Orekhov, A
International journal of molecular sciences. 2021;(16)
Abstract
Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.
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4.
Role of Telomeres Shortening in Atherogenesis: An Overview.
Yegorov, YE, Poznyak, AV, Nikiforov, NG, Starodubova, AV, Orekhov, AN
Cells. 2021;(2)
Abstract
It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis.
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5.
Evaluation of coronary plaques and atherosclerosis using optical coherence tomography.
Shimamura, K, Kubo, T, Akasaka, T
Expert review of cardiovascular therapy. 2021;(5):379-386
Abstract
Introduction: Coronary angiography (CAG) is the standard modality for assessing coronary stenosis; however, it has limitations in assessing coronary plaque morphology. Optical coherence tomography (OCT) is a high-resolution (10-20 μm) light-based intravascular imaging technique that can identify more detailed coronary plaque morphology compared to other intravascular imaging modalities. OCT is remarkable for characterizing fibrous, fibrocalcific, and lipid-rich plaques. The capabilities of OCT are well suited for discriminating three types of unstable plaque morphologies underlying coronary thrombosis, such as plaque rupture, erosion, and calcified nodules. The high resolution of OCT makes it possible to identify important features of vulnerable plaques, such as thin-cap (<65 μm thick) fibroatheroma, macrophages, vasa vasorum, and cholesterol crystals.Areas covered: This review summarizes the clinical impact of OCT and its efficacy in identifying plaque components and morphological features associated with plaque vulnerability.Expertopinion: The unique properties of OCT as a tool for investigating high-risk lesions have greatly contributed to a better understanding of plaque vulnerability. Consequently, OCT has led to significant changes in medical treatment and percutaneous coronary intervention strategies for acute coronary syndrome. Further development and investigation of OCT are necessary to better predict and manage acute coronary events in the future.
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6.
Sex-Related Differences in Cardiovascular Disease Risk Profile in Children and Adolescents with Type 1 Diabetes.
Smigoc Schweiger, D, Battelino, T, Groselj, U
International journal of molecular sciences. 2021;(19)
Abstract
Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, the underlying pathophysiology is not well understood. Atherosclerotic changes are known to progress early in life among people with T1D, yet it is less clear when excess CVD risk begins in females with T1D. This review explores the prevalence of classical CVD risk factors (such as glycemic control, hypertension, dyslipidemia, obesity, albuminuria, smoking, diet, physical inactivity), as well as of novel biomarkers (such as chronic inflammation), in children and adolescents with T1D with particular regard to sex-related differences in risk profile. We also summarize gaps where further research and clearer clinical guidance are needed to better address this issue. Considering that girls with T1D might have a more adverse CVD risk profile than boys, the early identification of and sex-specific intervention in T1D would have the potential to reduce later CVD morbidity and excess mortality in females with T1D. To conclude, based on an extensive review of the existing literature, we found a clear difference between boys and girls with T1D in the presence of individual CVD risk factors as well as in overall CVD risk profiles; the girls were on the whole more impacted.
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7.
PCSK9 and atherosclerosis: Looking beyond LDL regulation.
Ragusa, R, Basta, G, Neglia, D, De Caterina, R, Del Turco, S, Caselli, C
European journal of clinical investigation. 2021;(4):e13459
Abstract
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels.
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8.
[Molecular Mechanisms Underlying Toxic Actions of trans-Fatty Acids and Prevention of Related Diseases].
Matsuzawa, A
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2021;(5):675-679
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Abstract
trans-Fatty acids (TFAs), including elaidic acid and linoelaidic acid, are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. TFAs are not synthesized in the human body, but are taken into the body from various foods, which are mainly produced during industrial food manufacturing. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, such as atherosclerosis, cardiovascular diseases, allergic diseases, and dementia. However, the underlying pathogenic mechanisms of TFA-related disorders and the specific molecular targets evoking TFA toxicity are largely unknown. To elucidate the molecular mechanisms by which TFAs cause the cytotoxicity, we focused on cell death and inflammation, which are the main and common pathogenesis of the TFA-related diseases, and analyzed the effects of TFAs on cellular responses to various stimulations inducing cell death and inflammation. This review provides recent progress in our studies on the molecular mechanisms causing toxic actions of TFAs, which lead to diverse TFA-related disorders.
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9.
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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10.
Westernization of Lifestyle and Atherosclerosis in the Japanese: Lessons from the Hawaii - Los Angeles - Hiroshima Study.
Yoneda, M, Kubota, M, Watanabe, H, Egusa, G
Journal of atherosclerosis and thrombosis. 2021;(3):214-222
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Abstract
Japanese Americans include Japanese individuals migrating from Japan to the United States (first-generation Japanese Americans [JA-1]) and their offspring (second- or later-generation Japanese Americans [JA-2]). Although Japanese Americans share their genetic predisposition with the Japanese, their lifestyles have been westernized rapidly and extensively. We conducted a medical survey for atherosclerosis among Japanese Americans living in Hawaii and Los Angeles and native Japanese living in Hiroshima for 50 years since 1970 (the Hawaii-Los Angeles-Hiroshima Study) and obtained the following results:(1) In the 1990s, a westernized lifestyle induced hyperlipidemia among Japanese Americans, and based on the evaluation of the carotid artery intima-media wall thickness (IMT), atherosclerosis was apparently more advanced in Japanese Americans than in native Japanese. In addition, the advancement of atherosclerosis corresponded to the degree of westernization of lifestyles in JA-1 and JA-2.(2) In the 2010s, the serum total cholesterol and low-density lipoprotein cholesterol levels in native Japanese were significantly higher than those in Japanese Americans, and the difference in the progression of carotid artery IMT was smaller between native Japanese and Japanese Americans.(3) Maintaining a healthy Japanese lifestyle since childhood may suppress future worsening of risk factors for atherosclerosis (such as obesity and diabetes mellitus) and contribute to atherosclerosis prevention in the Japanese.