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)

Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolaemic diet; and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 (ref. 7), and crossed them with apolipoprotein (apo) E-null mice which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE-/- mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.
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PMID:Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. 973 72

Several observations suggest that cancer and atherosclerosis may entail fundamentally common biological mechanisms. The accumulation of lipids and the proliferation of smooth muscle cells (SMCs) are the main histological features of sclerotic plaque formation. The most prominent theory concerning the pathophysiological mechanisms of atherosclerotic plaque formation is the "inflammatory response to injury" hypothesis, which states that SMC proliferation is an inflammation-fibroproliferative reaction to different insults to the artery wall. However, recent evidence suggests that alterations at the DNA level may contribute significantly to the development of the disease. In accordance with these findings, the "monoclonal" hypothesis of atherosclerosis has been suggested. This hypothesis proposes that atherosclerosis begins as a mutation or viral infection, transforming a single, isolated smooth muscle cell into the progenitor of a proliferative clone, as seen in carcinogenesis. Studies of DNA damage in atherosclerotic tissues are lacking. Biological evidence for the hypothesis that cancer and atherosclerosis may share pathological mechanisms is discussed, emphasizing the need to perform studies investigating the involvement of somatic mutations in heart diseases.
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PMID:Genetic instability and atherosclerosis: can somatic mutations account for the development of cardiovascular diseases? 1086 45

Takayasu arteritis is a chronic vasculitis, mainly involving the aorta and its main branches as well as the coronary and pulmonary arteries, causing stenosis and/or obstruction due to thrombus formation or dilatation due to aneurysmal formation and/or rupture of the involved arteries. These characteristic anomalies resulted from ischemia of retinal arteries due to the obstruction of cervical vessels. In Western countries this disease is also known as "pulseless disease," because the pulse is frequently absent due to the obstruction of subclavian or branchial arteries. The pathogenesis of this morbid condition is still unknown. Epidemiologically, it is found mostly in female patients and is more prevalent in Asian and Latin American countries. Affected areas consist of a mixture of both active, productive inflammatory lesions, and old fibrous lesions. Autoimmune processes stimulated by viral infection and other unknown causative factors may play an important role under these pathophysiological conditions because HLA analysis revealed a statistically significant high frequency of haplotype A24-B52-DR2 in these patients in Japan. Documentation of atherosclerotic complications in young female patients with Takayasu arteritis who are generally free from traditional atherosclerosis risk factors may be clinical evidence that inflammation is indeed an important risk factor in atherogenesis.
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PMID:Inflammation and atherosclerosis. Atherosclerotic lesions in Takayasu arteritis. 1086 26

Takayasu arteritis, Buerger's diseases, temporal arteritis, vascular Behcet disease and inflammatory abdominal aortic aneurysm are classified in Japan as intractable vasculitides involving mainly large vessels, because their etiologies are not yet elucidated and, therefore, treatments for them were not yet established. Recent experimental and vascular biological studies, however, have focussed on the roles of virus infection in vasa vasorum (vasa vasoritis) and on the subsequent inflammatory vascular changes through HLA and/or other autoimmune mechanisms. Several studies including ours have demonstrated that these vascular inflammatory changes progress from the adventitial side to the intimal side of the vessel, finally complicating atherosclerotic changes in the intima. These vascular inflammatory changes are also recognized during progression of atherosclerosis and these observations strongly suggest that inflammation is a serious risk factor of atherosclerosis.
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PMID:Vasa vasoritis, vasculitis and atherosclerosis. 1098 Mar 30

Resveratrol (trans-3,5,4;-trihydroxystilbene) is a phytoalexin present in grapes, wine, and certain plants, which has recently been reported to possess properties that may protect against atherosclerosis, certain cancers, and inflammation. We now report that resveratrol (RV) synergistically enhances the anti-HIV-1 activity of the nucleoside analogues zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI). RV at 10 microM was not toxic to cells, and by itself reduced viral replication by 20% to 30%. In phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMCs) infected with HTLV-IIIB, 10 microM RV reduced the 90 % inhibitory concentration (IC90) of AZT, ddC, and ddI by 3.5-, 5.5-, and 17.8-fold, respectively. Similar antiviral activity was demonstrated when ddI was combined with 5 or 10 mM RV in PBMCs infected with clinical isolates of HIV-1. The addition of RV resulted in a >10-fold augmentation of ddI-antiviral activity in infected monocyte-derived macrophages (MDMs). In a resting cell model of T lymphocytes which were infected with HTLV-IIIB, RV plus ddI in combination, but not individually, suppressed establishment of a productive viral infection. In addition, RV plus ddI markedly inhibited the replication of four ddI-resistant viral isolates, three of which presented mutations in the RT gene conferring RT-multidrug resistance. Finally, when compared with hydroxyurea (HU), both 100 mM HU and 10 mM RV showed similar enhancement of ddI-antiviral suppressive activity. However, RV was shown to have less of a cellular antiproliferative effect than HU.
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PMID:Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol. 1111 55

The transcription factor NF-kappaB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-kappaB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-kappaB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-kappaB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-kappaB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-kappaBalpha (inhibitory protein that dissociates from NF-kappaB), due to inhibition of I-kappaB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-kappaBalpha phosphorylation, and NF-kappaB activation. The results identify p38 as an intracellular target for high dose vitamin C.
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PMID:Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. 1112 Aug 50

Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS-related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre-clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus.
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PMID:Recent strategies in the development of new human cytomegalovirus inhibitors. 1130 12

Over the last few years emerging evidence indicate the involvement of herpes viruses in the pathogenesis of several medical complications in transplanted patients. Herpes viruses are transmitted via inter-human contact and cause a primary infection, which commonly fails to give clinical signs and may persist even for years in a latent state in healthy subjects. In transplanted patients, herpes viruses may be transmitted through the transplanted organ or may be reactivated because of the use of powerful immunosuppressive drugs. Moreover, the persistence of immunosuppression greatly favours the clinical expression and severity of virus infection. Thus, herpes viruses seem to be involved in both acute and chronic deterioration of graft function, in the pathogenesis of post-transplant lymphoproliferative disorders and Kaposi sarcoma, and even in vessel atherosclerosis. This review will focus on relevant clinical aspects of herpes-virus infection, namely cytomegalovirus, EBV, herpes simplex 1 and 2, varicella zoster virus, HHV-6, HHV-7 and HHV-8, in kidney transplanted patients.
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PMID:[Herpetic viruses and renal transplantation]. 1219

Controlled trials suggest that acyclovir/valacyclovir can provide significant clinical benefits when used for prophylaxis in the immunocompromised host. These findings implicate herpesvirus(es) in the pathogenesis of complex medical conditions, including graft rejection and death. However, it is not known which of the 8 herpesviruses are important under particular circumstances. Prime candidates for triggering adverse outcomes are cytomegalovirus (CMV) in solid organ transplant recipients (causing rejection), CMV and human herpesvirus type 6 (HHV-6) in bone marrow transplant patients (causing marrow suppression), and herpes simplex virus, HHV-6, and CMV in AIDS patients (accelerating the rate of human immunodeficiency virus disease progression and death). Other diseases that may have a herpesvirus component or trigger susceptible antiviral agents include atherosclerosis and multiple sclerosis. In the future, clinicians should be alert to novel findings of randomized trials that may provide insight into the pathogenesis of these diseases and the contributions made by clinically silent herpesvirus infections.
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PMID:Tomorrow's challenges for herpesvirus management: potential applications of valacyclovir. 1235 98

Viral infection of the vascular wall cellular elements is involved in development of several pathophysiological events, including vasculitis, transplant rejection, and atherosclerosis. Previously, we have shown that cultured human vascular endothelial cells (ECs) may be effectively infected with herpes simplex type I virus (HSV-1), and this cultural model could be a useful tool for the explanation of many aspects of viral disease. In this study, we investigated the effects of conditioned media (CM) of peripheral blood mononuclear cells (PBMCs) on HSV-1 reproduction and cell adhesion molecule expression in cultured ECs. PBMC-CM induced the delay of virus reproduction or inhibition of virus reproduction. Effects of CM correlated with multiplicity of infection used for EC, time of PBMC contact with infected and glutaraldehyde-fixed endothelium, and the level of IFNs and cytokine production. Passages of and CM-treated and infected cells without signs of virus reproduction were, sometimes, followed by virus reactivation. However, at a low level of infection of CM-treated ECs the virus reactivation was not observed even after 2-3 cell passages. Neutralizing antibodies against IFN-alpha, IFN-gamma, and TNF-alpha, used separately or together, significantly abrogated the delaying and/or inhibiting action of CM. Additionally, PBMC-CM significantly increased the expression of ICAM-1 and VCAM-1 on cultured ECs. The strongest cell activation was induced by CM obtained from PBMCs co-incubated with virus-infected endothelium. Obtained results suggest that primed leukocytes produce soluble factors with either anti-viral or pro-inflammatory activity, and the effect of PBMC-CM may have a bi-directional action. On the one hand, due to production of interferons and several cytokines CM sets up HSV-1 latency or virus elimination from cultured cells. On the other, the same cytokines act on infected and/or neighboring ECs and initiate the cascade of inflammatory reactions in the vascular wall.
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PMID:Herpes simplex type I virus infected human vascular endothelial cells induce the production of anti-viral and proinflammatory factors by peripheral blood leukocytes in vitro. 1268 53


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