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)

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that binds to its sole counterreceptor, CXCR4. It is well reported that the SDF-1/CXCR4 signaling pathway is of vital importance to human development and to various pathophysiological phenomena, including hematopoiesis, angiogenesis, atherosclerosis, cancer growth, metastasis, and human immunodeficiency virus infection. SDF-1 promotes mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the circulation in response to vascular injury. Recently, we found that platelets express and release SDF-1 into the microcirculation upon activation and we observed that platelet-derived SDF-1 is functionally involved in recruitment of EPCs to arterial thrombi in vivo. This review discusses the unique functions of this chemokine and the newly discovered impact of platelet-derived SDF-1 into the recruitment of progenitor cells to vascular injury areas, and its subsequent effects in atherosclerosis, vascular repair, and angiogenesis.
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PMID:Platelets and stromal cell-derived factor-1 in progenitor cell recruitment. 1734 Apr 64

The role of various inflammatory mechanisms and oxidative stress in the development of atherosclerosis and arterial hypertension (AH) has been increasingly acknowledged during recent years. Hypertension per se or factors that cause hypertension along with other complications lead to infiltration of activated leukocytes in the vascular wall, where these cells contribute to the development of vascular injury by releasing cytokines, oxygen radicals, and other toxic mediators. However, molecular mechanisms underlying leukocyte activation at transcriptional level in AH are still far from being clear. To solve this problem we employed cDNA microarray technology to reveal the differences in gene expression in peripheral blood leukocytes from patients with AH compared with healthy individuals. The microarray data were verified by a semi-quantitative RT-PCR method. We found 25 genes with differential expression in leukocytes from AH patients among which 21 genes were upregulated and 4 genes were downregulated. These genes are implicated in apoptosis (CASP2, CASP4, and CASP8, p53, UBID4, NAT1, and Fte-1), inflammatory response (CAGC, CXCR4, and CX3CR1), control of MAP kinase function (PYST1, PAC1, RAF1, and RAFB1), vesicular trafficking of molecules among cellular organelles (GDI-1 and GDI-2), cell redox homeostasis (GLRX), cellular stress (HSPA8 and HSP40), and other processes. Gene expression pattern of the majority of genes was similar in AH patients independent of the disease stage and used hypotensive therapy, but was clearly different from that of normotensive subjects.
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PMID:Altered gene expression pattern in peripheral blood leukocytes from patients with arterial hypertension. 1734 25

The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.
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PMID:MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. 1743 71

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

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

Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.
Atherosclerosis 2008 Nov
PMID:SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. 1838 92

The cytokine macrophage migration inhibitory factor (MIF) is a unique pro-inflammatory regulator of many acute and chronic inflammatory diseases. In the pathogenesis of atherosclerosis, chronic inflammation of the arterial wall characterized by chemokine-mediated influx of leukocytes plays a central role. The contribution of MIF to atherosclerotic vascular disease has come into focus of many studies in recent years. MIF is highly expressed in macrophages and endothelial cells of different types of atherosclerotic plaques, and functional studies established the contribution of MIF to lesion progression and plaque inflammation. This proatherogenic effect may partly be explained by the finding that MIF regulates inflammatory cell recruitment to lesion areas. Similar to chemokines, MIF induces integrin-dependent arrest and transmigration of monocytes and T cells. These chemokine-like functions are mediated through interaction of MIF with the chemokine receptors CXCR2 and CXCR4 as a non-canonical ligand. In atherogenic monocyte recruitment, MIF-induced monocyte adhesion involves CD74 and CXCR2, which form a signaling receptor complex. In addition to lesion progression, MIF has been implicated in plaque destabilization, since MIF is predominantly expressed in vulnerable plaques and can induce collagen-degrading matrix metalloproteinases. The latter could be a relevant mechanism in atherosclerotic abdominal aneurysm formation, where MIF expression is correlated with aneurysmal expansion. In summary, MIF has been identified as an important regulator of atherosclerotic vascular disease with exceptional chemokine-like functions. Detailed analysis of the interaction of MIF with its receptors could provide valuable information for drug development for the anti-inflammatory treatment of established and unstable atherosclerosis.
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PMID:Chemokine-like functions of MIF in atherosclerosis. 1838 67

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.
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PMID:Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis. 1847 72


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