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:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
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PMID:Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review). 985 3

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
Hypertension 1999 Jan
PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

An excessive production of extracellular matrix (ECM) proteins in glomerular mesangial cells is considered to be responsible for the development of mesangial expansion seen in diabetic nephropathy. Mechanical stretch due to glomerular hypertension has been proposed as one of the factors leading to an increase in the production of ECM proteins in mesangial cells, but the precise mechanism of stretch-induced overproduction of ECM proteins has not been elucidated. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) may play a key role in the overproduction of fibronectin (FN) in mesangial cells exposed to mechanical stretch. MAPK, also termed extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), was activated by mechanical stretch in time- and intensity-dependent manners. Stretch-induced activation of ERK was inhibited by herbimycin A, a tyrosine kinase inhibitor, but not by GF109203X or calphostin C, the inhibitors of protein kinase C. Mechanical stretch also enhanced DNA-binding activity of AP-1, and this enhancement was inhibited by PD98059, an inhibitor of MAPK or ERK kinase (MEK). Furthermore, mechanical stretch stimulated the expression of FN mRNA followed by a significant increase in its protein accumulation. PD98059 could prevent stretch-induced increase in the expression of FN mRNA and protein. These results indicate that the activation of ERK may mediate the overproduction of ECM proteins in mesangial cells exposed to mechanical stretch, an in vitro model for glomerular hypertension seen in diabetes.
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PMID:Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase. 1007 62

Endothelin-1 (ET-1), a 21-amino acid vasoactive peptide mainly produced by vascular endothelial cells, is involved in the regulation of vascular tone and smooth muscle cell proliferation. Peroxisome proliferator-activated receptors (PPARs), key players in lipid and glucose metabolism, have been implicated in metabolic disorders that are predisposing to atherosclerosis. Because of the potential role of ET-1 in vascular disorders such as hypertension and atherosclerosis, we investigated the regulation of ET-1 expression by PPAR activators. Western blot and reverse transcription-polymerase chain reaction analyses demonstrated that both PPARalpha and PPARgamma are expressed in human coronary artery endothelial cells as well as in endothelial cell lines such as HMEC-1 and ECV304. In bovine aortic endothelial cells and HMEC-1 cells, both PPARalpha and PPARgamma ligands inhibited thrombin-induced ET-1 secretion, whereas basal ET-1 secretion was only slightly suppressed. Reverse transcription-polymerase chain reaction experiments showed that this inhibition of ET-1 production occurs at the gene expression level. Using transient transfection assays, we demonstrated that PPARs downregulate thrombin-activated transcription of the human ET-1 promoter. Transactivation studies with c-Jun and c-Fos expression plasmids indicated that PPARs negatively interfere with the activator protein-1 signaling pathway, which mediates thrombin activation of ET-1 gene transcription. Furthermore, electrophoretic mobility shift assays demonstrated that PPAR activators reduce the thrombin-stimulated binding activity of bovine aortic endothelial cell nuclear extracts as well as c-Jun binding to an activator protein-1 consensus site. Taken together, these data indicate that (1) both PPARalpha and PPARgamma are expressed in human vascular endothelial cells and (2) PPAR activators inhibit thrombin-induced ET-1 biosynthesis, indicating a novel role for PPARs in vascular endothelial function.
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PMID:Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. 1047 69

The in vivo role of mitogen-activated protein kinases (MAPK) in the development of glomerular injury is poorly understood. In the present study, glomerular MAPK activities, including extracellular signal-regulated kinases (ERK), c-Jun NH2-terminal kinases (JNK), and transcriptional factor, activator protein-1 (AP-1) were examined in glomerular injury of salt-induced hypertensive rats. Six-week-old Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were maintained on a high-salt (8.0% NaCl) diet for 1, 5, and 10 wk. In Dahl-S rats, as shown by in-gel kinase assay, an increase in BP by a high-salt diet was followed by chronic activation of glomerular ERK and JNK, which continued until 10 wk after a high-salt diet. Western blot analysis demonstrated a significant increase in the protein expression of glomerular ERK and JNK in Dahl-S rats fed a high-salt diet. As determined by gel-mobility shift assay, ERK and JNK activations were associated with an increase in glomerular AP-1 DNA binding activity. On the other hand, in Dahl-R rats fed a high-salt diet, BP remained normal throughout the experiments. However, glomerular ERK and JNK activities and AP-1 DNA binding activity in Dahl-R rats were not affected by 1 or 5 wk of a high-salt diet, but significantly increased by 10 wk of treatment with a high-salt diet, indicating that chronic sodium overload itself stimulated glomerular ERK and JNK and AP-1 activities. These kinase activations in both Dahl-S and Dahl-R rats were accompanied by an increase in urinary protein excretion and renal growth. These observations provide the first evidence that salt-sensitive hypertension causes chronic activation of glomerular ERK and JNK, probably leading to the activation of AP-1. Thus, glomerular MAPK may be responsible for the development of salt-induced glomerular injury.
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PMID:Chronic activation of glomerular mitogen-activated protein kinases in Dahl salt-sensitive rats. 1061 38

Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction of gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences.
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PMID:Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. 1074 85

Mechanical force is an important modulator of cellular morphology and function in a variety of tissues, and is particularly important in cardiovascular systems. Vascular smooth muscle cell (VSMC) hypertrophy and proliferation contribute to the development of atherosclerosis, hypertension, and restenosis, where mechanical forces are largely disturbed. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. Recently, it has been demonstrated that mechanical stress rapidly induced phosphorylation of platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once mechanical force is sensed, protein kinase C and mitogen-activated protein kinases (MAPKs) were activated, leading to increased c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. Interestingly, physical forces also rapidly resulted in expression of MAPK phosphatase-1 (MKP-1), which inactivates MAPKs. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signalling pathways, usually used by growth factors. These findings have significantly enhanced our knowledge of the pathogenesis of arteriosclerosis and provided promising information for therapeutic interventions for vascular diseases.
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PMID:Mechanical stress-initiated signal transductions in vascular smooth muscle cells. 1098 77

In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH(2)-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT(1)) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT(1) receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT(1) receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT(1) receptor-mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
Hypertension 2000 Oct
PMID:Important role of angiotensin II-mediated c-Jun NH(2)-terminal kinase activation in cardiac hypertrophy in hypertensive rats. 1104 Feb 28

Mitogen-activated protein (MAP) kinases are important intracellular mediators for proliferation and hypertrophy and therefore may also regulate cardiomyoblast growth in hypertensive heart disease. Thus, the aim of the present study was to examine the activities of MAP kinases, namely extracellular signal-regulated kinase (ERK)1,2, c-Jun NH2-terminal kinases (JNK)1,2 and p38 MAP kinase, in myocardial tissue of 12-week-old Prague normotensive (PNR) and hypertensive rats (PHR), a model of genetic hypertension with marked cardiac hypertrophy. Systolic blood pressure was 121 +/- 5 in PNR and 208 +/- 15 mm Hg in PHR (p < 0.01). Total heart weight was 247 +/- 4 in PNR vs. 316 +/- 4 mg/100 g body weight in PHR (p < 0.01). Left and right ventricular weights were 121 +/- 5 and 53 +/- 3 in PNR vs. 168 +/- 4 (p < 0.01) and 57 +/- 2 mg/100 g body weight (n.s.) in PHR. Using anti-ERK2 Western blot analysis as well as immunocomplex ERK activity assay, we found no activation of ERK2 in left or right ventricular tissue of PHR and PNR. Similary, p38 MAP kinase phosphorylation and activity were not detectable. In contrast, Western blot analysis using antiphospho-JNK antibodies revealed in myocardial tissue of right and left ventricles significantly greater phosphorylation of JNK2 in PHR than in PNR. This finding was confirmed by immunocomplex JNK activity assay using ATF-2 as substrate, which demonstrated a significant increase in JNK activity in the left ventricle of PHR as compared to PNR (6.4 +/- 1.5 vs. 2.5 +/- 0.5 OD; each n = 5; p < 0.05). In conclusion, cardiac JNK2 seems to be regulated differently from ERK2 in this rat model. In PHR, as compared to PNR, we found enhanced activity of JNK2 in the left and right ventricles suggesting that JNK2 is involved in hypertensive cardiac disease. The rise in JNK in both ventricles may result indirectly from humoral stimuli, e.g., endothelin-1 and/or angiotensin II, and may contribute to ventricular hypertrophy in this model of spontaneous hypertension.
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PMID:Cardiac hypertrophy in the Prague-hypertensive rat is associated with enhanced JNK2 but not ERK tissue activity. 1117 7

The role of mitogen-activated protein kinase (MAPK) pathways as signal transduction intermediates of hemodynamic stress leading to cardiac hypertrophy in the adult heart is not fully established. In a rat model of pressure-overload hypertrophy, we examined whether activation of MAPK pathways, namely, the extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and the p38-MAPK pathways, occurs during rapid changes in hemodynamic load in vivo. A slight activation of ERK2 and marked increases in JNK1 and p38-MAPK activities were observed 30 minutes after aortic banding. The increase in p38-MAPK activity was accompanied by an increase in the phosphorylation of the p38 substrate MAPK-activated protein kinases 2 and 3. Activation of these kinases was coincident with an increase in phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and enhanced DNA binding of activator protein-1 factors. Thus, hemodynamic stress of the adult rat heart in vivo results in rapid activation of several parallel MAPK kinase cascades, particularly stress-activated MAPK and p38-MAPK and their target transcription factors c-Jun and ATF-2.
Hypertension 2001 May
PMID:Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load. 1135 32


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