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Atherosclerosis is a subject of enormous contention for cardiologists and in general for all medical doctors. With this publication we have given you a concise ""state-of-the-art"" look at the world of atheroma. Many other elements could be included and so it is only a brief analysis of ""today"" (the preventive medicine era) and ""tomorrow"" (transforming the cure medicine era into the care medicine era) but also remembering ""yesterday"" (the ex-cathedra medicine era). Let's hope our arteries are free from atherosclerotic events: have a good read!

Atherosclerosis. --- Arteriosclerosis --- Medicine --- Cardiology and Cardiovascular Medicine --- Health Sciences

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Macrophages have unique and diverse functions necessary for survival. And, in humans (and other species), they are the most abundant leukocytes in tissues. The Innate functions of macrophages that are best known are their unusual ability to either “Kill” or “Repair”. Since killing is a destructive process and repair is a constructive process, it was stupefying how one cell could exhibit these 2 polar – opposite functions. However, in the late 1980’s, it was shown that macrophages have a unique ability to enzymatically metabolize Arginine to Nitric Oxide (NO, a gaseous non – specific killer molecule) or to Ornithine (a precursor of polyamines and collagen for repair). The dual Arginine metabolic capacity of macrophages provided a functional explanation for their ability to kill or repair. Macrophages predominantly producing NO are called M1 and those producing Ornithine are called M2. M1 and M2 – dominant responses occur in lower vertebrates, and in T cell deficient vertebrates being directly driven by Damage and Pathogen Associated Molecular Patterns (DAMP and PAMP). Thus, M1 and M2 are Innate responses that protect the host without Adaptive Immunity. In turn, M1/M2 is supplanting previous models in which T cells were necessary to “activate” or “alternatively activate” macrophages (the Th1/Th2 paradigm). M1 and M2 macrophages were named such because of the additional key findings that these macrophages stimulate Th1 and Th2 – like responses, respectively. So, in addition to their unique ability to kill or repair, macrophages also govern Adaptive Immunity.All of the foregoing would be less important if M1 or M2 – dominant responses were not observed in disease. But, they are. The best example to date is the predominance of M2 macrophages in human tumors where they act like wound repair macrophages and actively promote growth. More generally, humans have become M2 – dominant because sanitation, antibiotics and vaccines have lessened M1 responses. And, M2 dominance seems the cause of ever - increasing allergies in developed countries. Obesity represents a new and different circumstance. Surfeit energy (e.g., lipoproteins) causes monocytes to become M1 dominant in the vessel walls causing plaques.Because M1 or M2 dominant responses are clearly causative in many modern diseases, there is great potential in developing the means to selectively stimulate (or inhibit) either M1 or M2 responses to kill or repair, or to stimulate Th1 or Th2 responses, depending on the circumstance. The contributions here are meant to describe diseases of M1 or M2 dominance, and promising new methodologies to modulate the fungible metabolic machinery of macrophages for better health.

Microbiology & Immunology --- Biology --- Health & Biological Sciences --- Infection --- wound --- innate immunity --- M1 --- M2 --- Atherosclerosis --- macrophage --- Cancer

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Atherosclerosis and thrombosis are a major source of morbidity and mortality in the modern world. Great advances have been made in the past decades in our understanding of the pathophysiology of atherosclerosis and thrombus formation. This book offers a broad, contemporary review of atherosclerotic processes, with the latest research advances on inflammation and hypercoagulability that lead to thrombosis. In addition, experimental protocols are included, by which atherosclerotic processes are studied, providing the reader with the information necessary to understand the complexity of the disease process and the current experimental methodology in finding new answers that would help in the diagnosis, prevention and treatment of atherosclerotic disease.

Thrombosis. --- Atherosclerosis. --- Arteriosclerosis --- Blood --- Cardiovascular system --- Protein C deficiency --- Protein S deficiency --- Coagulation --- Diseases --- Endocrinology

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Warburg effect --- aerobic glycolysis --- Cellular metabolism --- Cancer --- Immunity --- Atherosclerosis --- Inflammation --- Angiogenesis

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It is by now widely recognized that atherosclerosis – with its burden of consequences in cerebro- and cardiovascular diseases – is just a chronic inflammatory process of the arterial wall. A very peculiar, complex and as yet still poorly understood process, upon which hundreds of scientists from several different fields are continuously concentrating their investigative efforts in search of possible leads to therapeutic approaches. Initiation of the disease is given by deposition of lipid in the intimal layers, resulting in endothelial activation and infiltration of blood-derived mononuclear cells. These mature into macrophages, become activated, express scavenger receptors such as SR-A and CD36 and ingest the oxidized lipoprotein accumulating in the lesion. Macrophages thus represent an obvious target for intervention, as they play a crucial role in the progression of the atherosclerotic inflammation. Studies have shown that hypercholesterolaemia can increase monocyte mobilisation from bone marrow into the circulation, and several chemokines and their receptors are involved in the recruitment of blood borne monocytes into the arterial wall. Monocyte-derived macrophages are capable of sustaining their local proliferation, but resident macrophages possibly also participate in progression of the disease. Remarkably, smooth muscle cells can acquire macrophage-like features during atherogenesis, including the ability to uptake lipid, thus becoming a significant proportion of the CD68+ so called ‘foam cells’. Lipid-laden macrophages induce extracellular matrix degradation, while lipid uptake eventually causes their death with formation of a necrotic core. The efficiency in clearance of dead cells by phagocytes (efferocytosis), can also be considered as a determinant of plaque vulnerability. An important feature of macrophages is their great plasticity and functional diversity in response to signals from the plaque microenvironment. Several such ‘signals’ (cholesterol, oxidative stress, hypoxia, cytokines…) can in fact modulate cell differentiation at transcriptional and epigenetic levels, thus altering the balance between the effector vs. reparative functions of macrophages. A whole gamut of specific subsets are thus originated, which appear to be simultaneously present in lesions with proportions that vary according to their location, the disease stage, and the presence of additional cell types such as e.g. dendritic cells. The result is a multiplicity of potential pharmacological targets, representing a major obstacle for the devisement of therapeutic strategies. Experimental approaches have been attempted in diverse directions: e.g. modulating the macrophage phenotype to an anti-inflammatory and resolving state, or blocking pro-inflammatory cytokines that macrophages produce, or alternatively enhancing efferocytosis in order to favour the resolution of inflammation and stabilization of plaques. Blocking monocyte recruitment was proposed in order to hinder the initial steps of atherogenesis. Other treatments were aimed to inhibiting local proliferation of pro-inflammatory macrophages. Specific targeting of macrophages has however to date not yet provided significant, translational results. The present Research Topic collects articles to help unravel the complexity of macrophage behaviour in atherosclerosis and identify innovative pharmacological approaches.

monocytes/macrophages --- inflammation --- foam cell formation --- smooth muscle cells --- atherosclerosis progression