Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.
...
PMID:Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. 1807 65

It has been reported that oxidized low density lipoprotein (Ox-LDL) can activate both peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma. However, the detailed mechanisms of Ox-LDL-induced PPARalpha and PPARgamma activation are not fully understood. In the present study, we investigated the effect of Ox-LDL on PPARalpha and PPARgamma activation in macrophages. Ox-LDL, but not LDL, induced PPARalpha and PPARgamma activation in a dose-dependent manner. Ox-LDL transiently induced cyclooxygenase-2 (COX-2) mRNA and protein expression, and COX-2 specific inhibition by NS-398 or meloxicam or small interference RNA of COX-2 suppressed Ox-LDL-induced PPARalpha and PPARgamma activation. Ox-LDL induced phosphorylation of ERK1/2 and p38 MAPK, and ERK1/2 specific inhibition abrogated Ox-LDL-induced COX-2 expression and PPARalpha and PPARgamma activation, whereas p38 MAPK-specific inhibition had no effect. Ox-LDL decreased the amounts of intracellular long chain fatty acids, such as arachidonic, linoleic, oleic, and docosahexaenoic acids. On the other hand, Ox-LDL increased intracellular 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) level through ERK1/2-dependent overexpression of COX-2. Moreover, 15d-PGJ(2) induced both PPARalpha and PPARgamma activation. Furthermore, COX-2 and 15d-PGJ(2) expression and PPAR activity were increased in atherosclerotic lesions of apoE-deficient mice. Finally, we investigated the involvement of PPARalpha and PPARgamma on Ox-LDL-induced mRNA expression of ATP-binding cassette transporter A1 and monocyte chemoattractant protein-1. Interestingly, specific inhibition of PPARalpha and PPARgamma suppressed Ox-LDL-induced ATP-binding cassette transporter A1 mRNA expression and enhanced Ox-LDL-induced monocyte chemoattractant protein-1 mRNA expression. In conclusion, Ox-LDL-induced increase in 15d-PGJ(2) level through ERK1/2-dependent COX-2 expression is one of the mechanisms of PPARalpha and PPARgamma activation in macrophages. These effects of Ox-LDL may control excess atherosclerotic progression.
...
PMID:Oxidized low density lipoprotein activates peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma through MAPK-dependent COX-2 expression in macrophages. 1820 15

Oxidation of low density lipoprotein (LDL) occurs in vivo and significantly contributes to the development of atherosclerosis. An important mechanism of LDL oxidation in vivo is its modification with 12/15-lipoxygenase (LO). We have developed a model of minimally oxidized LDL (mmLDL) in which native LDL is modified by cells expressing 12/15LO. This mmLDL activates macrophages inducing membrane ruffling and cell spreading, activation of ERK1/2 and Akt signaling, and secretion of proinflammatory cytokines. In this study, we found that many of the biological activities of mmLDL were associated with cholesteryl ester (CE) hydroperoxides and were diminished by ebselen, a reducing agent. Liquid chromatography coupled with mass spectroscopy demonstrated the presence of many mono- and polyoxygenated CE species in mmLDL but not in native LDL. Nonpolar lipid extracts of mmLDL activated macrophages, although to a lesser degree than intact mmLDL. The macrophage responses were also induced by LDL directly modified with immobilized 12/15LO, and the nonpolar lipids extracted from 12/15LO-modified LDL contained a similar set of oxidized CE. Cholesteryl arachidonate modified with 12/15LO also activated macrophages and contained a similar collection of oxidized CE molecules. Remarkably, many of these oxidized CE were found in the extracts of atherosclerotic lesions isolated from hyperlipidemic apoE(-/-) mice. These results suggest that CE hydroperoxides constitute a class of biologically active components of mmLDL that may be relevant to proinflammatory activation of macrophages in atherosclerotic lesions.
...
PMID:Cholesteryl ester hydroperoxides are biologically active components of minimally oxidized low density lipoprotein. 1826 82

Platelet hyperactivity associated with hyperlipidemia may contribute to development of a prothrombotic state. We previously showed that oxidized low-density lipoprotein (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis activated platelets in a CD36-dependent manner. We now show that mitogen-activated protein kinase c-Jun N-terminal kinase (JNK)2 and its upstream activator MKK4 were phosphorylated in platelets exposed to oxLDL. Using apoE(-/-) mice as a model of hyperlipidemia, we showed that JNK was constitutively phosphorylated in platelets in a CD36-dependent manner. Inhibition of src kinase activity reduced JNK phosphorylation by oxLDL. Immunoprecipitations revealed that active phosphorylated forms of src kinases Fyn and Lyn were recruited to CD36 in platelets exposed to oxLDL. Pharmacological inhibition of the mitogen-activated protein kinase JNK or src family kinases abolished platelet activation by oxLDL in vitro. Using a murine carotid artery thrombosis model we demonstrated CD36-dependent phosphorylation of platelet JNK within thrombi. Furthermore, pharmacological inhibition of JNK prolonged thrombosis times in wild-type but not cd36-null mice in vivo. These findings suggest that a specific CD36-dependent signaling pathway is required for platelet activation by oxLDL and may provide insights related to development of novel antiplatelet therapies more relevant to atherothrombosis than to normal hemostasis.
...
PMID:A specific CD36-dependent signaling pathway is required for platelet activation by oxidized low-density lipoprotein. 1849 30

Endothelial activation is a central initiating event in atheroma formation. Evidence from our laboratory and others has demonstrated links between activation of early growth response-1 (Egr-1) and atherosclerosis and also has demonstrated that activated protein kinase C (PKC) betaII is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKCbeta in regulating key events linked to atherosclerosis and show that the aortas of apoE(-/-) mice display an age-dependent increase in PKCbetaII antigen in membranous fractions vs. C57BL/6 animals with a approximately 2-fold increase at age 6 wk and a approximately 4.5-fold increase at age 24 wk. Consistent with important roles for PKCbeta in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKCbeta(-/-)/apoE(-/-) vs. apoE(-/-) mice by approximately 5-fold, in parallel with significantly reduced vascular transcripts for Egr-1 and matrix metalloproteinase (MMP)-2 antigen and activity vs. apoE(-/-) mice. Significant reduction in atherosclerosis of approximately 2-fold was observed in apoE(-/-) mice fed ruboxistaurin chow (PKCbeta inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKCbeta-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKCbeta may be beneficial in mitigating endothelial perturbation and atherosclerosis.
...
PMID:Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis. 1903 58

Apolipoprotein E-deficient (apoE(-/-)) mice have been shown to have increased vulnerability to neuronal damage induced by cerebral ischemia; however, the mechanism of this increased vulnerability remains unclear. In order to define the role of the apoE protein against ischemia-induced ER stress and cell death, experiments were performed to compare ER stress-associated chaperones and signal proteins in the hippocampus of apoE(-/-) mice to those of WT mice after being subjected to forebrain ischemia and reperfusion. Although neuronal loss in area CA1-CA3 of the hippocampus was observed 3 days after ischemia in both types of mice, the damage in apoE(-/-) mice was more severe. In apoE(-/-) mice, a more extensive increase in 78-kDa glucose-regulated protein (GRP78) was observed after the insult, whereas the level of GRP94 was not changed. The expression of both C/EBP homologous protein (CHOP) and caspase-12 was increased in the hippocampus in both WT and apoE(-/-) mice after ischemia. The increased levels of CHOP in apoE(-/-) mice were significantly higher than those in WT mice, whereas the levels of caspase-12 in the two were comparable. Furthermore, whereas the levels of c-Jun N-terminal kinase (JNK), p-JNK1 and p-JNK2 in WT mice were unchanged after ischemia, they were significantly increased in apoE(-/-) mice 24h and 48h after ischemia. These results suggest that increased vulnerability of the hippocampus to forebrain ischemia and reperfusion in apoE(-/-) mice is at least partly attributable to perturbed induction of an ER chaperone, GRP 94, and enhancement of the CHOP- and JNK-dependent apoptotic pathway in the hippocampus.
...
PMID:Apolipoprotein E-deficient mice are more vulnerable to ER stress after transient forebrain ischemia. 1942 81

The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR) mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure.
...
PMID:ApoE isoform-dependent changes in hippocampal synaptic function. 1972 29

Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 muM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway.
...
PMID:Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition. 2010 34

Adipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in A-FABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis.
...
PMID:Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1. 2014 51

Previous studies have shown that apoE (apolipoprotein E) expression in macrophages suppresses inflammatory responses; however, whether endogenously synthesized apoE acts intracellularly or after its secretion in suppressing macrophage inflammation remains unclear. The present study used the murine monocyte macrophage cell line RAW 264.7 to examine the influence of exogenous apoE on macrophage inflammatory responses induced by TLR (Toll-like receptor)-4 and TLR-3 agonists LPS (lipopolysaccharide) and poly(I-C) respectively. Results showed that exogenously added apoE suppressed the LPS and poly(I-C) induction of IL (interleukin)-6, IL-1beta and TNF-alpha (tumour necrosis factor-alpha) secretion by RAW 264.7 cells. The mechanism was related to apoE suppression of TLR-agonist-induced phosphorylation of JNK (c-Jun N-terminal kinase) and c-Jun. A peptide containing the tandem repeat sequence of the receptor-binding domain of apoE, apoE-(141-155)2, was similarly effective in inhibiting LPS- and poly(I-C)-induced macrophage inflammatory responses. Reductive methylation of lysine residues in apoE, which abolished its receptor-binding capability without affecting its ability to interact with HSPGs (heparin sulfate proteoglycans), inhibited the ability of apoE to suppress macrophage responses to LPS, but had no effect on apoE suppression of poly(I-C)-induced macrophage activation. The ability of apoE to suppress poly(I-C)-induced pro-inflammatory cytokine production was abolished by heparinase treatment of RAW 264.7 cells to remove cell-surface HSPGs. Taken together, these results indicate that exogenous apoE inhibits macrophage inflammatory responses to TLR-4 and TLR-3 agonists through distinct mechanisms related to receptor and HSPG binding respectively, and that these inhibitory effects converged on suppression of JNK and c-Jun activation which are necessary for macrophage activation.
...
PMID:Apolipoprotein E inhibits toll-like receptor (TLR)-3- and TLR-4-mediated macrophage activation through distinct mechanisms. 2021 69


<< Previous 1 2 3 4 5 6 Next >>

---