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

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.
 ...
PMID:TNF blockade: an inflammatory issue. 1633 57

Our understanding of the molecular signaling pathways regulating the initiation and progression of atherosclerosis or remodeling in response to injury has begun to cross the boundaries from regulation of well-described canonical pathways to the interplay between these pathways. The focus of this review is to summarize our current understanding of a finite group of transcription factors and kinases involved in vascular injury and atherosclerosis, including nuclear factor-kappaB (NF-kappaB), early growth response factor-1 (Egr-1), activator protein-1 (AP-1), hypoxia inducible factor-1alpha (HIF-1alpha), homeobox, and T cell factor/lymphoid enhancer factor (Tcf-Lef), as well as the kinases janus kinase/signal transducers and activators of transcription (JAK/STAT), protein kinase C (PKC), p38, Rho, ERK5, JNK, p44/p42, and phosphoinositide 3 (PI3) kinase/AKT.
 ...
PMID:Transcription factor and kinase-mediated signaling in atherosclerosis and vascular injury. 1664 Sep 63

Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in angiopoietin-1 (Ang-1)-induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 microM) and apocynin (200 microM) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although Ang-1 stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells, the responses were strikingly suppressed in cells from the p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.
 ...
PMID:Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. 1667 92

In this study we examined the ability of tissue factor (TF) alone, or in conjunction with factor VIIa, factor Xa and TFPI in activating a number of key signalling pathways associated with cellular growth, stress and differentiation responses in human endothelial cells. We used luciferase reporter systems to demonstrate the activation of p42/44 MAPK by the TF-FVIIa complex, mediated via the PAR1 receptor. TF alone was capable of interacting with the cell surface and was sufficient to activate the JNK-SAPK pathway and subsequently AP-1, but the level of activation was enhanced by the activity of FXa on PAR1 and 2. Furthermore, the phosphorylated form of the transmembrane-cytoplasmic domain of TF was directly responsible for activation of these pathways. CREB activation occurred in response to TF-FVIIa in a non-protease dependent manner but was lowered on addition of FXa. Finally, NFkappaB activation occurred in response to FVIIa or FXa, with the latter exhibiting higher levels of activation. In conclusion, we have shown that TF is capable of activating differing signalling pathways, via more than one mechanism. The differential influence of TF is modified depending on the presence of other coagulation factors and ultimately acts as a deciding factor in the determination of cellular fate.
Atherosclerosis 2007 Sep
PMID:Differential functions of tissue factor in the trans-activation of cellular signalling pathways. 1713 81

Ras has a key role in relation to cell proliferation, survival and migration and requires farnesylation for full activity. The effects of a Ras farnesyl transferase inhibitor, FPT III on human atherosclerotic vascular smooth muscle (VSM) cells proliferation and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) activity was measured. In addition the ability of FPT III to modify the development of neointimal growth was tested in cultured human arteries and in a rabbit model of in-stent restenosis. In human VSM cells FPT III (25 microM) inhibited FCS-stimulated cell proliferation through a ras-dependent mechanism (after 18 h exposure) and also a novel ras-independent mechanism (following 15 min exposure). FPT III incubation (18 h) inhibited platelet-derived growth factor (PDGF)-stimulated p42/p44 MAPK activation and p21 Ras membrane localization, whereas 15 min incubation had no effect on the activation of p42/p44 MAPK in response to PDGF (added at 18 h) or on membrane p21 Ras localization (measured at 18 h). In cultured human atherosclerotic arteries, the presence of 25 microM FPT III significantly reduced neointimal growth. In vivo, 15 min local infusion of 25 microM FPT III significantly reduced in-stent restenosis 28 days later without affecting vascular function in normal rabbit artery. This study demonstrates that brief administration of a farnesyl transferase inhibitor reduced in-stent restenosis in a rabbit model without deleterious effects on vascular function or endothelial regrowth. Acute application of FPT III was found to act through a novel mechanism to inhibit smooth muscle cell proliferation via a non-ras pathway, which may contribute to the prevention of in-stent restenosis.
Atherosclerosis 2008 Apr
PMID:Inhibition of non-Ras protein farnesylation reduces in-stent restenosis. 1766 87

Non-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated. We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n = 9/group) were exposed to purified CRP (25 microg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1alpha, IL-1beta and IL-6, and the chemokines GRO-alpha, GRO-beta and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) alpha and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRalpha mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRalpha protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRalpha. Western blot analysis revealed CRP-induced nuclear translocation of NF-kappaB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRalpha mRNA expression was inhibited by anti-CD64 (FcgammaRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRalpha pathway.
 ...
PMID:C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor alpha, on human monocytes. 1832 90

Statins enhance incorporation of bone marrow-derived cells into experimental neointimal lesions. However, the contribution of progenitor cells to progression of spontaneous atherosclerotic plaques, and the possible modulatory role of statins in this process, remain poorly understood. We compared the effects of rosuvastatin (1 and 10mg/kg BW) and pravastatin (10mg/kg) on progenitor cell mobilisation, recruitment into atherosclerotic plaques, and lesion growth. Statins were administered over 8 weeks to apolipoprotein E knockout mice on atherogenic diet. In addition, mice were lethally irradiated, followed by transplantation of bone marrow from LacZ transgenic mice. Rosuvastatin reduced lesion area and intima-to-media ratio at the brachiocephalic artery compared to vehicle, while both parameters were not significantly altered by pravastatin. Rosuvastatin also augmented endothelialisation (P<0.05) and reduced the smooth muscle cells (SMC) content (P=0.042) of lesions. Numbers of c-kit, sca-1 and flk-1, sca-1 double-positive progenitor cells were significantly increased in rosuvastatin compared to control-treated mice, both in the bone marrow and the peripheral blood. Similarly, the number of spleen-derived acLDL, lectin double-positive progenitor cells (P=0.001) and colony-forming units (P=0.0104) was significantly increased in mice treated with rosuvastatin compared to vehicle alone. In the bone marrow, increased Akt and p42/44 MAP kinase phosphorylation and upregulated SDF1alpha mRNA expression were observed. Importantly, rosuvastatin treatment also increased the plasma levels of c-kit ligand (P=0.003), and the number of c-kit-positive cells within atherosclerotic lesions (P=0.041). Our findings suggest that rosuvastatin reduces the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilisation and recruitment into vascular lesions.
Atherosclerosis 2009 Jul
PMID:Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice. 1911 32

Neovascularization is critical to destabilization of atheroma. We previously reported that the angiogenic growth factor pleiotrophin (PTN) coaxes monocytes to assume the phenotype of functional endothelial cells in vitro and in vivo. In this study we show that PTN expression is colocalized with capillaries of human atherosclerotic plaques. Among the various reagents that are critical to the pathogenesis of atherosclerosis, interferon (IFN)-gamma was found to markedly induce PTN mRNA expression in a dose-dependent manner in macrophages. Mechanistic studies revealed that the Janus kinase inhibitors, WHI-P154 and ATA, efficiently blocked STAT1 phosphorylation in a concentration- and time-dependent manner. Notably, the level of phosphorylated STAT1 was found to correlate directly with the PTN mRNA levels. In addition, STAT1/STAT3/p44/42 signaling molecules were found to be phosphorylated by IFN-gamma in macrophages, and they were translocated into the nucleus. Further, PTN promoter analysis showed that a gamma-activated sequence (GAS) located at -2086 to -2078 bp is essential for IFN-gamma-regulated promoter activity. Moreover, electrophoretic mobility shift, supershift, and chromatin immunoprecipitation analyses revealed that both STAT1 and STAT3 bind to the GAS at the chromatin level in the IFN-gamma stimulated cells. Finally, to test whether the combined effect of STAT1/STAT3/p44/42 signaling is required for the expression of PTN in macrophages, gene knockdowns of these transcription factors were performed using siRNA. Cells lacking STAT1, but not STAT3 or p42, have markedly reduced PTN mRNA levels. These data suggest that PTN expression in the human plaques may be in part regulated by IFN-gamma and that PTN is involved in the adaptive immunity.-Li, F., Tian, F., Wang, L., Williamson, I. K., Sharifi, B. G., Shah, P. K. Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-gamma/JAK/STAT1 signaling is critical for the expression of PTN in macrophages.
 ...
PMID:Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-{gamma}/JAK/STAT1 signaling is critical for the expression of PTN in macrophages. 1991 72

Obesity is associated with insulin resistance in the peripheral vasculature and is an important risk factor for coronary artery disease. The current study assessed whether the vascular effects and the signaling pathways of insulin are impaired in coronary arteries from a rat model of genetic obesity. Intramyocardial arteries from obese Zucker rats (OZR) and lean Zucker rats (LZR) were mounted in microvascular myographs to assess insulin vasoactive effects and the proteins of the insulin pathway were determined by Western blotting. The endothelium-dependent and nitric oxide (NO)-mediated vasorelaxant effect of insulin was similar in arteries from LZR and OZR and blunted by inhibition of phosphatidylinositol 3-kinase (PI3K) and endothelial NO synthase (eNOS), but unaltered by either mitogen activated protein kinase (MAPK) or endothelin (ET) receptor blockade. Basal levels of phospho-eNOS Ser(1177) and phospho-Akt Ser(473) were up-regulated in OZR, and insulin increased phosphorylation of eNOS and Akt in both LZR and OZR. Moreover, insulin enhanced Akt expression in LZR. Basal and insulin-stimulated levels of phospho-MAPK p42/p44 were lower in OZR and palmitic acid reduced these levels in LZR. Coronary arteries are protected from vascular IR. The results underscore the fact that preservation of insulin-mediated vasorelaxation along with an up-regulation of the Akt/eNOS pathway and an impairment of the MAPK cascade account for this protection.
Atherosclerosis 2011 Aug
PMID:Preserved insulin vasorelaxation and up-regulation of the Akt/eNOS pathway in coronary arteries from insulin resistant obese Zucker rats. 2151 35

Caveolae are omega-shaped membrane invaginations present in essentially all cell types of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes, and fibroblasts. Numerous functions have been ascribed to this omega-shaped structure. Caveolae are enriched with different signaling molecules and ion channel regulatory proteins and function both in protein trafficking and signal transduction in these cell types. Caveolins are the structural proteins that are necessary for the formation of caveola membrane domains. Mechanistically, caveolins interact with a variety of downstream signaling molecules, as, for example, Src-family tyrosine kinase, p42/44 mitogen-activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS) and hold the signal transducers in the inactive condition until activated with proper stimulus. Caveolae are gradually acquiring increasing attention as cellular organelles contributing to the pathogenesis of several structural and functional processes including cardiac hypertrophy, atherosclerosis, and heart failure. At present, very little is known about the role of caveolae in cardiac function and dysfunction, although recent studies with caveolin knock-out mouse have shown that caveolae and caveolins play a pivotal role in various human pathobiological conditions. This review will discuss the possible role and mechanism of action of caveolae and caveolins in different cardiac diseases.
 ...
PMID:Caveolae, caveolin, and cavins: potential targets for the treatment of cardiac disease. 2165 41


<< Previous 1 2 3 4 5 Next >>