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)

Type IIA secretory phospholipase A(2) (sPLA(2)) is an acute-phase reactant that plays a role in atherogenesis and is expressed in atherosclerotic arterial walls displaying inflammatory features. This generates a relevant question addressing the biological effects of this enzyme on monocytic cells, in view of the role of these cells in the inflammatory process associated with atherosclerosis. sPLA(2) produced a mild activation of the p42 mitogen-activated protein module of the mitogen-activated protein kinase (MAPK) cascade and a prominent activation of c-Jun N-terminal kinase in THP-1 monocytes. This activation showed both an early and a late peak, different from that elicited by tumor necrosis factor-alpha (TNF-alpha), which only showed the first peak. This was accompanied by activation of arachidonate metabolism, as judged from both the activation of the cytosolic phospholipase A(2) (cPLA(2)) and the induction of cyclooxygenase-2 (COX-2) expression. sPLA(2) also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF-alpha on both COX-2 induction and MCP-1 production. sPLA(2) upregulated the expression of Fas ligand at the cell surface, but it did not influence Fas expression nor cell survival of monocytes. In summary, these data indicate that some of the atherogenic effects of sPLA(2) can be exerted by engagement of an sPLA(2)-binding structure on monocytic cells, most probably the M-type receptor for sPLA(2), which produces the activation of the MAPK cascade, induces a proinflammatory phenotype, and upregulates the cell surface expression of Fas ligand.
 ...
PMID:Secretory phospholipase A(2) elicits proinflammatory changes and upregulates the surface expression of fas ligand in monocytic cells: potential relevance for atherogenesis. 1178 16

Apoptosis is a form of genetically programmed cell death, which plays a key role in regulation of cellularity in a variety of tissue and cell types including the cardiovascular tissues. Under both physiological and pathophysiological conditions, various biophysiological and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc., may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions, and mediates vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of atherosclerotic plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.
 ...
PMID:Molecular signal transduction in vascular cell apoptosis. 1178 70

Traditional thinking accorded a major role to deranged cell proliferation as a determinant of the abnormal cellularity of atheroma. However, studies conducted in several laboratories have documented the occurrence of disordered apoptosis during atherogenesis, leading to the death of lipid-rich foam cells (promoting lipid-core formation) and depletion of vascular smooth muscle cells (fostering fragility of the fibrous cap). A complex interplay of environmental factors and endogenous proteins regulates apoptosis and contributes to the struggle between cell death and procreation in atherosclerosis. In addition to a variety of growth factors, chemically modified lipids, reactive oxygen species, proinflammatory cytokines, and Fas ligand produced by activated immune cells may influence cell viability through a diversity of pathways, including the caspase cascade, the Bcl-2 protein family, and the oncogene/antioncogene system. A clarification of the molecular mechanisms responsible for vascular cell death may aid in the development of novel therapeutic strategies to treat atherosclerosis and its complications, including the acute coronary syndromes.
 ...
PMID:Progression of atheroma: a struggle between death and procreation. 1223 54

Under normal conditions, vascular endothelial cells are resistant to Fas-mediated apoptosis, although they express detectable Fas on their cell surface. Because oxidized Low density lipoprotein (Ox-LDL) is thought to promote atherogenesis, the potential role that Ox-LDL may play in Fas-mediated apoptosis was investigated in human umbilical vascular endothelial cells (HUVECs), focusing particularly on the involvement of the lectin-like Ox-LDL receptor-1 (LOX-1). HUVECs were treated with agonistic anti-Fas antibody (CH11) and Ox-LDL and then the degree of apoptosis was determined by cell death ELISA. Ox-LDL concentration-dependently sensitized Fas-mediated apoptosis. Flow cytometry demonstrated that Ox-LDL dose-dependently up-regulated cell surface Fas expression. On the other hand, treating HUVECs with Ox-LDL did not lead to any significant change in the expression of death mediators, including Fas, Fas ligand (FasL), FADD, and FLICE as assessed by multiplex polymerase chain reaction amplification. More importantly, these effects of Ox-LDL on Fas-mediated apoptosis were significantly blocked by a neutralizing LOX-1 monoclonal antibody, which can block LOX-1-mediated cellular uptake of Ox-LDL. Ox-LDL may be an important factor involved in the regulation of Fas-induced apoptosis via Ox-LDL/LOX-1 interaction in vascular endothelial cells. The results may provide insights into the pathogenesis of accelerated atherosclerosis in patients with hyperlipidemia.
 ...
PMID:Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells. 1241 41

IL-18 is a pleiotropic cytokine and is produced by various types of cells including activated macrophages, particularly Kupffer cells. IL-18 has potential to activate inflammatory responses through induction of IFN-gamma production in collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity to induce allergic responses via induction of IL-4 production by T helper cells and to activate mast cells and basophils to release atopic effector molecules such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries, such as Crohn's disease and atherosclerosis, and also in hyper IgE and atopic dermatitis. IL-18 is particularly important for induction of experimental liver diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and primary biliary cirrhosis show elevation of serum levels of IL-18, that correlates with the corresponding disease severity. Therefore, endogenous IL-18 plays a major role in induction of some types of liver injuries in mice and human. NKT cells that express both T cell receptor and NK cell marker are abundant in the liver of mice and human. Recent studies have revealed that NKT cells participate in some types of liver injuries, such as concanavalin A-induced T cell-mediated hepatitis and malaria hepatitis. In this review article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver injuries.
 ...
PMID:Cytokine-induced inflammatory liver injuries. 1452 86

Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by alpha-tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
 ...
PMID:Regulation of gene expression by alpha-tocopherol. 1531 6

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
 ...
PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Oxidative stress is one of the major risk factors for coronary artery disease. Ellagic acid is a phenolic compound present in fruits and nuts, and has been found to have antioxidative property. Twenty-four New Zealand white (NZW) rabbits were assigned randomly into four dietary groups. The normal group was fed regular rabbit chow, and the cholesterol group was fed a high fat and cholesterol diet. The ellagic acid (E) group and probucol group were fed the same diet as the cholesterol group plus the addition of 1% (w/w diet) ellagic acid and probucol, respectively. Oxidative stress [as measured by plasma lipids, oxygen free radicals and thiobarbituric acid reactive substances (TBARS)] increased in the cholesterol group compared with the normal group; however, it decreased in the probucol and E groups compared with the cholesterol group. Forty-five percent of the intimal surface of the thoracic aorta was covered with atherosclerotic lesions in the cholesterol group, but only 2-3% was covered in the E and probucol groups. The aortic level of 8-(OH)dG and the expression of caspase-8, caspase-9 and Fas ligand were also suppressed after ellagic acid supplement. These results indicated that ellagic acid could prevent atherosclerosis via suppression of oxidative stress and apoptosis in hyperlipidemic rabbits.
 ...
PMID:Reduction of oxidative stress and apoptosis in hyperlipidemic rabbits by ellagic acid. 1608 Dec 67

In addition to well-documented vascular growth-promoting effects, ANG II exerts proapoptotic effects that are poorly understood. IGF-1 is a potent survival factor for human vascular smooth muscle cells (hVSMC), and its antiapoptotic effects are mediated via the IGF-1 receptor (IGF-1R) through a signaling pathway involving phosphatidylinositol 3-kinase and Akt. We hypothesized that there would be cross talk between ANG II proapoptotic effects and IGF-1 survival effects in hVSMC. To investigate ANG II-induced apoptosis and the potential involvement of IGF-1, we exposed quiescent and nonquiescent hVSMC to ANG II. ANG II induced apoptosis only in nonquiescent cells but stimulated hypertrophy in quiescent cells. ANG II-induced apoptosis was characterized by marked inhibition of Akt phosphorylation and stimulation of membrane Fas ligand (FasL) expression, caspase-8 activation, and a reduction in soluble FasL expression. Adenovirally mediated overexpression of Akt rescued hVSMC from ANG II-induced apoptosis. IGF-1R activation increased Akt phosphorylation and soluble FasL expression, and these effects were completely blocked by coincubating hVSMC with ANG II. In conclusion, ANG II-induced apoptosis of hVSMC is characterized by marked inhibition of Akt phosphorylation and stimulation of an extrinsic cell death signaling pathway via upregulation of membrane FasL expression, caspase-8 activation, and a reduction in soluble FasL expression. Furthermore, ANG II antagonizes the antiapoptotic effect of IGF-1 by blocking its ability to increase Akt phosphorylation and soluble FasL. These findings provide novel insights into ANG II-induced apoptotic signaling and have significant implication for understanding ANG II-induced remodeling in hypertension and atherosclerosis.
 ...
PMID:ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. 1633 40

Oxidative stress and apoptosis are 2 major characteristics of the progression of atherosclerosis. Both lovastatin and Magnolia officinalis are hypocholesterolemic agents. Therefore, we investigated the effect of M. officinalis extract on the prevention of atherosclerosis in comparison with lovastatin. Twenty hyperlipidemic rabbits were served one of the following diets: a high-fat and cholesterol diet (cholesterol group, 10% corn oil and 0.5% cholesterol), a high fat and cholesterol diet supplemented with M. officinalis extract (300 mg/kg) or lovastatin (6 mg/kg). The plasma lipids, oxidative stress (measured by free radical, malondialdehyde, and oxidative DNA damage), and arterial lesions significantly decreased in the M. officinalis and lovastatin groups when compared with the cholesterol group. Moreover, the expressions of Fas ligand, caspase 8, and caspase 9 in the aortic arches were also markedly lowered after M. officinalis and lovastatin supplements. Therefore, the results indicate that the antiatherogenic effect of M. officinalis is involved with a suppression of oxidative stress and with the down-regulation of apoptosis-related gene expression in hyperlipidemic rabbits.
 ...
PMID:Inhibitory effect of Magnolia officinalis and lovastatin on aortic oxidative stress and apoptosis in hyperlipidemic rabbits. 1663 91


<< Previous 1 2 3 4 Next >>