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)

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.
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PMID:Opposite role of pro-inflammatory alleles in acute myocardial infarction and longevity: results of studies performed in a Sicilian population. 1680 97

Inflammation plays a central role in vascular repair, and spreads into perivascular tissue (PVT) following angioplasty. Chemokines (CK) and chemokine receptors (CKR) are key determinants of inflammatory chemotaxis. We sought to assess the arterial and perivascular expression of the CK CCL2 and CXCL2, and the CKR CCR2, CCR5, and CXCR4 in balloon-injured porcine coronary arteries. Vascular cells that express specific CK and CKR mRNA during post-angioplasty time course were detected by in situ hybridization (ISH), and expression was quantified by real time RT-PCR in PVT. CCL2 was maximal in PVT from 2 to 24h post injury, coincident with local macrophage-activation. Expression was upregulated in media and adventitia from 24h to 3 days, and in neointima at 7 days. CXCL2 was detected in media at 2 and 4h, and also in some neointimal cells. CCR2 and CCR5 were maximal in PVT at 24h and 3 days, respectively. Expression shifted to media and adventitia at 2 and 3 days, and to neointima and adventitia at 7 days, and was low at 14 days. CXCR4 was low in PVT, but was upregulated in media and adventitia at 2 and 3 days, as well as in neointima and adventitia at 7 days. In conclusion, PVT is the primary source of inflammatory CK and CKR early post-angioplasty. Specific sequential patterns of CK- and CKR-synthesis are identified that may regulate phase-specific chemotaxis by spatio-temporally differential expression during coronary response to injury.
Atherosclerosis 2007 May
PMID:Sequential patterns of chemokine- and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries. 1692 16

Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE(-/-) mice and skewed toward an increased frequency of CCR2(+)Ly-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell-associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2(-) monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE(-/-) mice. By comparison, CCR2(+)Ly-6C(hi) monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2(+) monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.
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PMID:Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. 1720 Jul 12

Fractalkine/CX3CR1 pathway is considered a major modulator of atherosclerosis. In the present study, expression of CX3CR1 on PBMCs/monocytes of healthy individuals and coronary artery diseased patients was initially assessed by flow cytometry. Effects of pre-inflammatory cytokines interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha on expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) were further assessed in three cell models: THP-1 monocytes, Jurkat T lymphocytes and primary monocytes isolated from healthy donors. Finally, effects of angiotensin-converting enzyme (ACE) inhibitors captopril, lisinopril and angiotensin receptor blocker (ARB) losartan on chemokine receptor expression were evaluated in the same cell models either in a naive or stimulated state. INF-gamma significantly affected the chemokine receptor phenotype of THP-1 cells by increasing the rate of CX3CR1-positive cells. Pre-treatment with the ACE inhibitors, captopril and lisinopril, and the ARB, losartan, did not influence these effects. Captopril and lisinopril similarly had no effect on either stimulated or naive primary monocytes. Yet, a small but repeatable increase in CX3CR1 expression after treatment with losartan was noted. Nevertheless, the latter observation did not retain statistical significance after applying the Bonferroni correction. In conclusion, our data did not indicate any significant effect of the ACE inhibitors on the chemokine receptor phenotype of monocytes.
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PMID:CX3CR1 receptor is up-regulated in monocytes of coronary artery diseased patients: impact of pre-inflammatory stimuli and renin-angiotensin system modulators. 1752 10

In arteriosclerosis, activated T cells infiltrating the atherosclerotic lesions are directly involved in the pathogenesis of these vascular disorders. Infiltration and accumulation of T cells into the vascular wall occur at the earliest stage of atherosclerosis. The atherosclerotic lesion also sees the accumulation of modified lipids such as lysophosphatidylcholine (lysoPC), the main phospholipid component of oxidized low-density lipoprotein. However, it remains less clear how lysoPC affects CD4 T cells. Therefore, we assessed the effect of lysoPC on various mRNA expressions in human T cells using real-time quantitative Reverse Transcription-PCR. Exposure of Jurkat cells (a human CD4 T-cell line) to lysoPC resulted in upregulation of CXCR4 and CCR5 chemokine receptors, receptor for oxidized low-density lipoprotein (LOX-1), the transcription factors, nuclear factor-kappa beta (NF-kB) and Yin Yang 1, and target molecules of NF-kB, A1/Bfl1/BCL2A1 and c-IAP1/BIRC2, in a dose-dependent manner. These data indicate that lysoPC is a positive regulator of the inflammatory response in human CD4 T cells. Further, it suggested that lysoPC and CD4 T cells accumulating in atherosclerotic lesions contribute to the development of arteriosclerosis.
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PMID:Lysophosphatidylcholine upregulates LOX-1, chemokine receptors, and activation-related transcription factors in human T-cell line Jurkat. 1796 22

Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states.
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PMID:Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways. 1816 90

This is a study to define the profile of chemokine receptors expressed on isolated infiltrating lymphocytes in human abdominal aortic aneurysms (AAAs), and to examine their role in lymphoid recruitment. AAA T-lymphocytes were CXCR4-positive, CCR7-negative and partially CXCR3 and CCR5-positive. Functionally, AAA T-cells were proinflammatory effector cells, as they produced IFN-gamma and granzyme A. AAA B-lymphocytes were CXCR4-positive and exhibited low CXCR5 expression. A relevant feature of infiltrating T- and B-lymphocytes was the high intensity of CXCR4 expression and the capability to migrate to CXCL12. CXCL12-producing cells were found in the adventitia of AAA. These cells were CD45-negative and partially VCAM-1 and DR-positive. In summary, the present results suggest that CXCR4, expressed on infiltrating lymphocytes, and CXCL12, expressed on stromal cells, is involved in the recruitment of lymphocytes within the arterial wall in AAA.
Atherosclerosis 2008 Oct
PMID:Chemokine receptor expression on infiltrating lymphocytes from abdominal aortic aneurysms: role of CXCR4-CXCL12 in lymphoid recruitment. 1828 Oct 50

Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. Hypotheses for these observations include: 1) an increase in the prevalence of established cardiac risk factors observed in HIV-infected individuals who are currently experiencing longer life expectancies; 2) the dyslipidemia reported with certain HIV anti-retroviral therapies; and/or 3) the proinflammatory effects of infiltrating HIV-infected monocytes/macrophages. An unexplored possibility is whether HIV itself can infect vascular smooth muscle cells (SMCs) and, by doing so, whether SMCs can accelerate vascular disease. Our studies demonstrate that human SMCs can be infected with HIV both in vivo and in vitro. The HIV protein p24 was detected by fluorescence confocal microscopy in SMCs from tissue sections of human atherosclerotic plaques obtained from HIV-infected individuals. Human SMCs could also be infected in vitro with HIV by a mechanism dependent on CD4, the chemokine receptors CXCR4 or CCR5, and endocytosis, resulting in a marked increase in SMC secretion of the chemokine CCL2/MCP-1, which has been previously shown to be a critical mediator of atherosclerosis. In addition, SMC proliferation appeared concentric to the vessel lumen, and minimal inflammation was detected, unlike typical atherosclerosis. Our data suggest that direct infection of human arterial SMCs by HIV represents a potential mechanism in a multifactorial paradigm to explain the exacerbated atherosclerosis and vasculopathy reported in individuals infected with HIV.
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PMID:Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. 1831 May 3

The chemokine receptor CCR5 is implicated in the pathogenesis of various inflammatory diseases, such as multiple sclerosis (MS), atherosclerosis, transplant rejection, and autoimmunity. In previous studies, we have shown that MS lesions are characterized by enhanced expression of transcription factors associated with stress responses, ie, IRF-1, NF-kappaB, and CREB-1, which modulate expression of both classes of major histocompatibility complex (MHC) molecules. The expression of MHC-I and MHC-II molecules greatly overlaps with the expression of CCR5 in MS lesions. Therefore, we investigated whether these factors are also involved in the transcriptional regulation of CCR5. Using in vitro assays, we determined that neither IRF-1 nor NF-kappaB is involved in the activation of the CCR5 promoter. This is corroborated by the finding that these factors are not involved in the induction of endogenous CCR5 transcription in various cell types. In contrast, we show that CCR5 expression is regulated by the cAMP/CREB pathway and that interference in this pathway affects endogenous CCR5 transcription. From this, we conclude that the cAMP/CREB pathway is involved in the regulation of CCR5 transcription and that, given the ubiquitous nature of CREB-1 protein expression, additional regulatory mechanisms must contribute to cell type-specific expression of CCR5.
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PMID:CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor. 1851 6

The fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site- and stage-specific effects of T cell-activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX(3)CL1 and CXCL16 with their respective receptors CX(3)CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected. The considerable leap in insight over recent years leads us to anticipate further advances in comprehending the role of chemokines in atherosclerosis, allowing targeted interventions for its prevention and therapy.
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PMID:Chemokines in atherosclerosis: an update. 1856 99


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