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

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemodynamic forces play a key role in inducing atherosclerosis-implicated gene expression in vascular endothelial cells. To elucidate the signal transduction pathway leading to such gene expression, we studied the effects of fluid shearing on the activities of upstream signaling molecules. Fluid shearing (shear stress, 12 dynes/cm2 [1 dyne = 10(-5)N]) induced a transient and rapid activation of p21ras and preferentially activated c-Jun NH2 terminal kinases (JNK1 and JNK2) over extracellular signal-regulated kinases (ERK-1 and ERK-2). Cotransfection of RasN17, a dominant negative mutant of Ha-Ras, attenuated the shear-activated JNK and luciferase reporters driven by 12-O-tetradecanoylphorbol-13-acetate-responsive elements. JNK(K-R) and MEKK(K-M), the respective catalytically inactive mutants of JNK1 and MEKK, also partially inhibited the shear-induced luciferase reporters. In contrast, Raf301, ERK(K71R), and ERK(K52R), the dominant negative mutants of Raf-1, ERK-1, and ERK-2, respectively, had little effect on the activities of these reporters. The activation of JNK was also correlated with increased c-Jun transcriptional activity, which was attenuated by a negative mutant of Son of sevenless. Thus, mechanical stimulation exerted by fluid shearing activates primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression.
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PMID:The Ras-JNK pathway is involved in shear-induced gene expression. 888 24

1. The mechanisms of the antiproliferative effect of epigallocatechin, one of the catechin derivatives found in green tea, in vascular smooth muscle cells were studied. The proliferative response was determined from the uptake of tritiated thymidine. 2. In the concentration range of 10(-6) to 10(-4) M, catechin, epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin, epigallocatechin gallate, concentration-dependently inhibited the proliferative response stimulated by serum in rabbit cultured vascular smooth muscle cells. Catechin and epicatechin were less effective in inhibiting the serum-stimulated smooth muscle cell proliferation, indicating that the galloyl group may be important for full inhibitory activity. 3. Epigallocatechin (EGC) inhibited the proliferative responses in different cells including rat aortic smooth muscle cells (A7r5 cells), rabbit cultured aortic smooth muscle cells, human coronary artery smooth muscle cells, and human CEM lymphocytes in a concentration-dependent manner. The possible mechanisms of the antiproliferative effect of EGC were further studied in A7r5 cells. 4. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by 10(-5) M EGC. In contrast, the cytosolic protein kinase C activity stimulated by phorbol ester was unaffected by directly incubating with EGC (10(-6)-10(-4) M). 5. We also performed Western blot analysis using the anti-phosphotyrosine monoclonal antibody PY20. EGC (10(-5) M) reduced the levels of tyrosine phosphorylated proteins with different molecular weights, indicating that EGC may inhibit the protein tyrosine kinase activity or stimulate the protein phosphatase activity. 6. Reverse transcription-polymerase chain reaction analysis of c-fos, c-jun and c-myc mRNA levels demonstrated that c-jun mRNA level after serum-stimulation was significantly reduced by 10(-5) M EGC. However, the reduction of c-fos and c-myc mRNA levels by 10(-5) M EGC did not achieve significance. 7. Western blot analysis using the antibody against JNK (c-jun N-terminal kinase) and ERK (extracellular signal-regulated kinase) demonstrated that the level of phosphorylated JNK1, but not phosphorylated ERK1 and ERK2, was reduced by 10(-5) M EGC. Direct measurement of kinase activity by immune complex kinase assay confirmed that JNK1 activity was inhibited by EGC treatment. These results demonstrate that EGC preferentially reduced the activation of JNK/SAPK (stress-activated protein kinase) signal transduction pathway. 8. It is suggested that the antiproliferative effect of epigallocatechin on vascular smooth muscle cells may partly be mediated through inhibition of protein tyrosine kinase activity, reducing c-jun mRNA expression and inhibiting JNK1 activation. Tea catechins may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis.
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PMID:Epigallocatechin suppression of proliferation of vascular smooth muscle cells: correlation with c-jun and JNK. 972 Jul 95

Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH(2)-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
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PMID:Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. 1206 26

In vitro studies suggest a role for c-Jun N-terminal kinases (JNKs) in proatherogenic cellular processes. We show that atherosclerosis-prone ApoE-/- mice simultaneously lacking JNK2 (ApoE-/- JNK2-/- mice), but not ApoE-/- JNK1-/- mice, developed less atherosclerosis than do ApoE-/- mice. Pharmacological inhibition of JNK activity efficiently reduced plaque formation. Macrophages lacking JNK2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SR-A), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of JNK2 was sufficient to decrease atherogenesis. Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.
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PMID:Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. 1556 63

The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.
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PMID:Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. 1605 42

Numerous studies in animal models established a key role of the C-jun N-terminal kinase (JNK) family (JNK1, JNK2 and JNK3) in numerous pathological conditions, including cancer, cardiac hypertrophy and failure, neurodegenerative disorders, diabetes, arthritis and asthma. A possible function of JNK in atherosclerosis remained uncertain since conclusions have mainly been based on in vitro studies investigating endothelial cell activation, T-effector cell differentiation and proliferation of vascular smooth muscle cells, all of which represent crucial cellular processes involved in atherosclerosis. However, recent experiments demonstrated that macrophage-restricted deletion of JNK2 was sufficient to efficiently reduce atherosclerosis in mice. Furthermore, it has been shown that JNK2 specifically promotes scavenger receptor A-mediated foam cell formation, an essential step during early atherogenesis, which occurs when vascular macrophages internalize modified lipoproteins. Thus, specific inhibition of JNK2 activity may emerge as a novel and promising therapeutic approach to attenuate atheroma formation in the future. In this review, we discuss JNK-dependent cellular and molecular mechanisms underlying atherosclerosis.
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PMID:"Jnking" atherosclerosis. 1623 Oct 89

Hyperglycemia, advanced glycation end products (AGEs), hyperinsulinemia and dyslipidemia may play roles in the development of diabetes-associated atherosclerosis and post-angioplasty restenosis. Clinically, their effects seem to be synergic. However, few studies have focused on the synergistic action of these factors. In the present study, we investigated whether glycated serum albumin (GSA) has a synergistic effect with insulin on the proliferation of vascular smooth muscle cells (VSMCs). VSMCs were isolated from rat thoracic aortas and cultured in fetal bovine serum (FBS)-free medium for 24 h, then exposed to GSA, insulin or GSA + insulin for 48 h with or without pretreatment of mitogen-activated protein kinase (MAPK) inhibitors or the antioxidant N-acetylcysteine (NAC). Cell growth rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or cell counting. The changes of phosphorylated-p38 MAPK and phosphorylated-C-Jun N-terminal kinase 1/2 (JNK1/2) were measured by Western blot analysis. The results showed that only p38 MAPK, but not JNK was activated by GSA and insulin co-incubation. VSMC proliferation was increased by insulin (10-1000 nmol/L) or GSA (10, 100 microg/mL). Co-incubation of insulin (100 nmol/L) and GSA (100 mug/mL) caused a more potent increase in VSMC proliferation than insulin or GSA incubation alone. p38 MAPK inhibitor, SB203580, as well as NAC, could inhibit the VSMC proliferation induced by co-incubation of GSA and insulin. The results show that insulin enhances GSA-induced VSMC proliferation, which may be mediated through a reactive oxygen species (ROS)-p38 MAPK pathway. The synergism of AGEs and insulin may play a detrimental role in the pathogenesis of diabetic atherosclerosis and post-angioplasty restenosis.
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PMID:Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells. 1729 35

The development of therapeutic strategies to inhibit reactive oxygen species (ROS)-mediated damage in blood vessels has been limited by a lack of specific targets for intervention. Targeting ROS-mediated events in the vessel wall is of interest, because ROS play important roles throughout atherogenesis. In early atherosclerosis, ROS stimulate vascular smooth muscle cell (VSMC) growth, whereas in late stages of lesion development, ROS induce VSMC apoptosis, causing atherosclerotic plaque instability. To identify putative protective genes against oxidative stress, mouse aortic VSMC were infected with a retroviral human heart cDNA expression library, and apoptosis was induced in virus-infected cells by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) treatment. A total of 17 different, complete cDNAs were identified from the DMNQ-resistant VSMC clones by PCR amplification and sequencing. The cDNA encoding PP1cgamma1 (catalytic subunit of protein phosphatase 1) was present in several independent DMNQ-resistant VSMC clones. DMNQ increased mitochondrial ROS production, caspase-3/7 activity, DNA fragmentation, and decreased mitochondrial transmembrane potential in VSMC while decreasing PP1cgamma1 activity and expression. Depletion of PP1cgamma1 expression by short hairpin RNA significantly enhanced basal as well as DMNQ-induced VSMC apoptosis. PP1cgamma1 overexpression abrogated DMNQ-induced JNK1 activity, p53 Ser(15) phosphorylation, and Bax expression and protected VSMC against DMNQ-induced apoptosis. In addition, PP1cgamma1 overexpression attenuated DMNQ-induced caspase-3/7 activation and DNA fragmentation. Inhibition of p53 protein expression using small interfering RNA abrogated DMNQ-induced Bax expression and significantly attenuated VSMC apoptosis. Together, these data indicate that PP1cgamma1 overexpression promotes VSMC survival by interfering with JNK1 and p53 phosphorylation cascades involved in apoptosis.
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PMID:Identification of a protective role for protein phosphatase 1cgamma1 against oxidative stress-induced vascular smooth muscle cell apoptosis. 1854 44

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.
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PMID:Beta-caryophyllene is a dietary cannabinoid. 1857 42

The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn's disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB(2)) receptor, which unlike the CB(1) receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB(1) receptor antagonists/inverse agonists are of therapeutic value, also CB(2) receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB(1) receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB(2) receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent anti-inflammatory effects in wild type mice but not in CB(2) receptor (Cnr2(-/-)) knockout mice. Like other CB(2) ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1beta, IL-6; IL-8 and TNFalpha) and promotes a TH(1) immune response. In this addendum, the CB(2) receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB(2) inverse agonists and agonists, independent of their G-protein signaling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.
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PMID:Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? 1970 83


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