Heart Inst

HIF 0 Comments

Heart Inst. in the arteries.3 With pioneering work from I. Ignatowski, A. Windaus, Versipelostatin and N. Anichkov in the early 1900s, a critical link between cholesterol and atherosclerosis was proposed.3 With the turn of the century, numerous studies have demonstrated that cholesterol and lipoproteins play a critical role in the development of atherosclerosis. The conceptual association between immune cells and the pathogenesis of atherosclerosis was raised KBTBD6 by Virchow as early as 1856;4 however, this hypothesis Versipelostatin did not crystallize until the latter half of the 20th century. In 1973, R. Ross and colleagues suggested the model, in which, localized injury within the artery was proposed to initiate the accumulation of smooth muscle cells, resulting in narrowing the arterial lumen.5 Conceptually, today atherosclerosis is a multifactorial disease of large and medium size vessels6-9 in which cholesterol rich lipoproteins are slowly retained within the arterial wall in conjunction with localized activation of vascular cells and the accumulation of immune cells (Fig.1). Open in a separate window Figure 1 The major steps in the development and progression of atherosclerosis. Atherosclerosis is a progressive, multifactorial inflammatory disease that encompasses endothelial activation, leukocyte recruitment, M activation and proliferation, and antigen presentation to T cells and ultimately results in elevated pro-inflammatory cytokine production, inflammation, and necrosis. Atherosclerosis is initiated by the deposition, retention, and modification of LDL in the intima, resulting in NF-BCdependent activation of the endothelium, the expression of adhesion molecules, chemokines, and the recruitment of Ly6Chi monocytes and pre-DCs to the intimal layer. Ly6Chi monocytes may subsequently differentiate to M or possibly DCs. Ms are the prominent cell type within the arterial wall, and several arterial macrophage subsets (M1, M2, M4, and Mox M, Figure 2) have been observed. Dendric cells and DC subsets (Flt3-dependent DCs, Flt3-independent DCs, and pDCs, not shown), while far less abundant, are similarly present. Ms and DCs scavenge for modified lipoproteins (or other potential self-antigens) within the arterial lumen by scavenger receptors and Toll-like receptors, and may present antigens to T cells to activate intra-plaque T helper (Th) 1 and Th17 cells, and thus to Versipelostatin further support leukocyte recruitment to the nascent plaque. Once activated, arterial Ms become either pro-inflammatory proteolytic M1 Ms, releasing IL-12, IL-1, and TNF-, or less inflammatory M2 Ms, releasing IL-10 and TGF-. DC subsets also support atherosclerotic low grade inflammation by the release of type 1 interferons, and activation/modulation of T cell responses. B cells, which are also present in atherosclerotic plaques, may support or suppress inflammation through the production of antibodies and cytokines. As Ms start to proliferate and as a result of persistent foam cells formation and reduced efferocytosis, the nascent plaque becomes an advanced atherosclerotic lesion, resulting in the formation of a calcified necrotic core. Upon the resolution of hypercholersterolemia, CD68+ cell egression from Versipelostatin the plaque through adventitial lymphatic vessels and efficient efferocytosis might result in regression of the lesion. Several populations of immune cells including B and T lymphocytes, eosinophils, macrophages (M), dendritic cells (DCs), neutrophils, and mast cells are involved in the progression of atherosclerosis, both within the arterial wall and secondary lymphoid tissues.10 Atherosclerosis develops in several stages. One of the initial steps in atherosclerosis is the accumulation of modified low density lipoproteins (LDLs) within the intima of arteries and their uptake by arterial M, which quickly become the major leukocyte population within nascent atheroclerotic plaques. 9 These events trigger the subsequent activation of endothelial and smooth muscle cells, resident lymphocytes, DCs, and elicits massive production of pro-inflammatory mediators, which accelerates leukocyte recruitment, induces chronic, low-grade inflammation, and likely an antigen-specific adaptive immune response.8 To date, it remains unclear whether the antigen-presentation occurs.