Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class A macrophage scavenger receptor (SR-A) is one of the major receptors of macrophages and plays important roles in atherogenesis and host defense mechanisms. To assess the role of SR-A, monoclonal antibodies were generated by immunizing SR-A-deficient mice with a recombinant protein of human type I SR-A as immunogen. Four antibodies (SRA-C6, SRA-D10, SRA-E5, and SRA-F8) were confirmed to be specific for SR-A by Western blot analysis. In early atherosclerotic lesions, these antibodies recognized scattered macrophages in intima and foamy macrophages in the periphery of atheromatous cores. Interestingly, foamy macrophages in the core lesion were only weakly stained. In other organs, the antibodies recognized tissue macrophages such as alveolar macrophages, Kupffer cells in the liver, red pulp macrophages in the spleen, sinus macrophages in lymph nodes, and interstitial macrophages in various organs. Perivascular macrophages in the brain (Mato cells) were also positive for these antibodies. Freshly isolated blood monocytes were negative; however, they became positive for these antibodies after 1 day in culture. At 3-5 days in culture, the reaction intensity became stronger along their differentiation towards macrophages. Dendritic cells such as interdigitating cells of lymphoid tissues and epidermal Langerhans cells were invariably negative. In the reaction with animal tissues, each antibody showed a unique reaction pattern. Among four antibodies, SRA-E5 recognized SR-A molecules in all animal species examined, including rats and mice. These antibodies will be useful tools for the study of SR-A in atherogenesis and various other pathological conditions in humans and animal species.
Atherosclerosis 2002 Mar
PMID:Production, characterization, and interspecies reactivities of monoclonal antibodies against human class A macrophage scavenger receptors. 1188 24

Osteopontin (OPN), a noncollagenous adhesive protein, may possibly be implicated in atherosclerosis, in which macrophages and activated T lymphocytes could have higher OPN levels within the atherosclerotic plaques. However, it is not known whether a higher OPN level is a cause or a result of atherosclerosis or whether it has a promoting or inhibitory effect on atherosclerosis. To clarify the role of OPN in atherosclerosis, we developed a transgenic mouse (OPN-TG) in which the exogenous OPN gene was designed to be expressed by hematopoietic cells, expressing OPN, which carried the immunoglobulin enhancer (Emu)/SV40 promoter. In OPN-TG, the expression of exogenously transfected OPN RNA was found in lymphoid organs, such as the thymus and spleen, and the kidney. In the present study, OPN-TG mice were assigned into two groups, an atherogenic diet group (15% fat, 1.25% cholesterol) for 3 months or a standard diet group (4% fat), and both groups were compared with wild-type C57BL/6 mice to investigate the relationship between osteopontin and the atherosclerotic lesion. In wild-type mice, OPN mRNA was detected in kidney, but not in lymphoid tissues. In both OPN-TG and wild-type mice fed with control diets, atherosclerotic lesions were not found in the aortic sinus or the thoracic and abdominal aorta. In both OPN-TG and wild-type mice fed with atherogenic diets, a high incidence of atherosclerotic lesions was noted in the aortic sinus. The atherosclerotic lesions were significantly larger in OPN-TG as compared with those in control littermate mice (size: 33.8% +/- 23.4% vs. 10.9% +/- 20.4%, respectively, P < 0.05). Activated foamy macrophages within atherosclerotic plaque in OPN-TG expressed a considerably larger amount of OPN compared with such macrophages in control mice. The OPN protein detected in the atherosclerotic lesions was not due to the deposition of serum OPN, but mainly due to in situ production by the infiltrating macrophages. Thus, these results suggest that OPN is atherogenic and that macrophages expressing OPN can be easily activated and thus promote atheromatous lesions if a high fat diet is consumed.
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PMID:Development of atherosclerosis in osteopontin transgenic mice. 1202 33

Coactivators such as cyclic AMP-response-element binding protein (CREB)-binding protein (CBP) and p300/CBP associated factor (P/CAF) play a crucial role in coordinating and cointegrating eukaryotic transcription. One of the recent paradigms in the eukaryotic transcription field is the finding of molecular basis of coactivator function. The well characterized coactivators such as CBP and P/CAF have been proposed to coactivate/cointegrate gene expression with many transcription activators through two mechanisms. One is complex formation with the components with basal transcriptional machinery. Another is its intrinsic and associated enzymatic activity, which transfers an acetyl-base to the epsilon ( epsilon ) portion of lysine-residues in histones and certain nuclear proteins (factor acetyltransferases; FATs), such as p53, lymphoid enhancer-binding factor (LEF), and transcription factor IIE (TFIIE), which often results in increased transcriptional activity. Recently, the status of hyper nuclear acetylation (HNA) has been thought to influence proliferation, differentiation and apoptosis. Furthermore, recent reports showed that histone acetyltransferase (HAT) activity is increased in human disease, such as cancer and atherosclerosis, and studies have shown associations between nuclear acetylation/deacetylation and cell proliferation/differentiation.
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PMID:Hyper nuclear acetylation (HNA) in proliferation, differentiation and apoptosis. 1272 76

Cellular infiltrates consisting mainly of lymphocytes are commonly present in the arterial wall in abdominal aortic aneurysm (AAA). However, despite this, the precise nature of these populations has to date not been described in detail. The aim of this study was to perform an exhaustive phenotypic characterisation of the infiltrating lymphocytes in order to define the inflammatory process that develops in AAA. For this purpose, AAA-infiltrating lymphocytes from 25 fresh aneurysm wall samples and, as a control, peripheral blood (PB) lymphocytes from the same patients were purified. The expression of lineage specific markers, maturation molecules, activation antigens and adhesion molecules on T and B lymphocytes was examined by triple-colour immunofluorescence and flow cytometry analysis. The phenotype of AAA-infiltrating lymphocytes was compared with that of PB of the patients with AAA. The results reveal that AAA-infiltrating B and T lymphocytes consist of activated memory cells, with specific homing properties. In addition, they express molecules of B-T co-stimulation and, occasionally, exhibit phenotypical features indicative of the ectopic formation of lymphoid structures. These findings are discussed in the light of the similarities shared with the lymphoid infiltration occurring in other chronic autoimmune/inflammatory disorders.
Atherosclerosis 2003 Sep
PMID:Characterisation of T and B lymphocytes infiltrating abdominal aortic aneurysms. 1295 81

Retinoid-related orphan receptors ROR alpha, -beta, and -gamma are evolutionarily related transcription factors belonging to the steroid hormone receptor superfamily. Studies of ROR mutant mice revealed that these receptors are critical in the regulation of a number of physiological processes. ROR alpha plays a key role in the development of the cerebellum particularly in the regulation of Purkinje cell differentiation and proliferation of granule cell progenitors. ROR alpha has also been implicated in the maintenance of bone tissue and mice deficient in ROR alpha exhibit a greater susceptibility to atherosclerosis. ROR gamma is essential for lymph node organogenesis and plays a key role in the generation or survival of lymphoid tissue inducer (Lti) cells. ROR gamma is also critical in thymopoiesis where it controls differentiation and promotes the survival of thymocytes by positively regulating Bcl-X(L) expression. Several studies have indicated a regulatory role for RORs in circadian behavior. In several tissues, the expression of RORs oscillates during circadian rhythm while mice deficient in ROR beta exhibit an altered circadian rhythm. ROR alpha and ROR gamma have been implicated in the control of various immune responses. Mice deficient in ROR gamma exhibit a reduced susceptibility to allergen-induced airway inflammation while ROR alpha null mice show a prolonged inflammatory response to lipopolysaccharide. Recent analyses of the crystal structure and transcriptional activity of RORs revealed that cholesterol and specific cholesterol derivatives behave as agonists of ROR alpha while certain retinoids function as partial antagonists of ROR beta and ROR gamma. These studies indicate that ROR activity and, as a consequence physiological processes regulated by RORs, can be modulated by exogenous (ant)agonists. Therefore, the discovery of new (ant)agonists may lead to the development of novel therapeutic strategies for human disease in which RORs have been implicated.
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PMID:Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs). 1558 88

Immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation, and apoptosis are pathological hallmarks of atherosclerosis. The multifocal, chronic, and inflammatory nature of this disease of the cardiovascular system complicates targeted cellular therapy and emphasizes the need to understand the role and interaction of immune cells with VSMCs. We characterized the immune cell subsets present in human atherosclerotic tissue derived from atherosclerotic abdominal aortic aneurysm (AAA) and expanded them to study their interaction with autologous plaque-derived VSMCs in vitro. We show here that apart from T lymphocytes, plaque infiltrates consist of lots of NK cells and significant proportions of NKT cells that express T cell receptor (TCR) alphabeta, CD4, and the NK markers CD56 and CD161. The infiltrates are predominantly IFN-gamma-producing Type 1 lymphoid cells. When cocultured, the T and NKT cells adhere to VSMCs. CD4+ T cells enhance VSMC proliferation. VSMCs in turn enhance CD4+CD161+ NKT but not CD4+ or CD8+ T cell proliferation. CD4+CD161+ NKT cells inhibit VSMC proliferation by inducing apoptosis. Our results suggest that the interactions of Type 1 CD4+ T and CD4+CD161+ NKT cells with VSMCs may regulate VSMC proliferation and death respectively in atherosclerosis and the balance of these interactions could determine plaque stability.
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PMID:Atherosclerotic abdominal aortic aneurysm and the interaction between autologous human plaque-derived vascular smooth muscle cells, type 1 NKT, and helper T cells. 1573 63

The paper demonstrates that lymph nodes situated in the vicinity of magistral blood vessels are the source of immune and inflammatory response to LDL as the main pathogenetic factor in atherosclerosis. The activation of T-cell-mediated immunity takes place in them at the very early stages of the disease, resulting in forming of CD4+T-lymphocytes, activated mononuclear cells and immunostabilizing B-lymphocytes. The cell changes in lymph nodes correlate with the severity of atherosclerotic lesions in the vessel intima and closely reflect the peculiarities of immune inflammation development in fatty streaks and atherosclerotic plaques in human atherogenesis. A paradoxical reaction was observed in cases with Chlamydia pneumoniae found in the wall of aorta and paraaortal lymph nodes. No evident immune response on the part of immunocompetent cells took place, but, on the contrary, the function of mononuclear cells, including T-lymphocytes, was suppressed. This phenomenon may be explained by the fact that intracellular localization of Chlamydia pneumoniae hides it from immune system control or by the possible microorganism capability of direct immunosuppressive influence on lymphoid cells both in the blood vessel wall and in regional lymph nodes.
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PMID:[The immune system, atherosclerosis and persisting infection]. 1577 61

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.
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PMID:Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. 1581 11

Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs were identified in arteries in 1995 and, since then, further knowledge has been gained indicating the importance of DCs in atherosclerosis. Vascular DCs have been shown to become activated from a very early stage of atherosclerosis. Some DCs cluster with T cells directly within atherosclerotic lesions, while others migrate to lymphoid organs to activate T cells. Dyslipidaemia systemically alters DC function and recent findings suggest that DCs play a role in plaque destabilization. This review summarizes the current status of the problem.
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PMID:Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. 1626 69

Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.
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PMID:Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms. 1592 98


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