Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an in vivo study, spontaneously hypertensive rats (SHR) were treated with an angiotensin II (Ang II) type 1 receptor antagonist of candesartan or hydralazine. Untreated SHR progressively developed severe hypertension, and treatment with candesartan or hydralazine decreased blood pressure. Candesartan reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, the relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine slightly prevented an increase in LV wall thickness, but did not exert a significant reduction on other parameters. In an in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes. Stretching cardiomyocytes activated second messengers such as protein kinase C, Raf-1 kinase, and mitogen-activated protein (MAP) kinase, increasing protein synthesis, enhancing endothelin (ET)-1 release, activating the Na+/H+ ion exchanger. Moreover, pretreatment with candesartan diminished an increase in phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. This suggests that the cardiac renin-angiotensin system is linked to the formation of pressure-overload hypertrophy and that Ang II increases the growth of cardiomyocytes by an autocrine mechanism. Finally, we examined the signalling pathways leading to MAP kinase activation both in cardiac myocytes and in cardiac fibroblasts. Ang II-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts, Ang II activated MAP kinase through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and protein kinase C were important in cardiac myocytes.
 ...
PMID:Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress. 1007 20

Angiotensin II and hypertension increase vascular oxidant stress. We examined how these might affect expression of the extracellular superoxide dismutase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis. This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1. d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase; however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderately increased transcriptional rate (as assessed by nuclear run-on analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative state of the vessel wall in pathological processes in which the renin-angiotensin system is activated.
 ...
PMID:Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. 1040 Sep 7

To determine a potential role for the renin-angiotensin system in the growth of human pulmonary artery (PA) smooth muscle, we studied the localization of angiotensin (ANG) II-receptor subtypes by autoradiography in sections of human PA and in cultured PA smooth muscle cells (PASMCs) and examined the growth responses to ANG II in vitro. Specific 125I-labeled [Sar1,Ile8]ANG II binding was demonstrated within the pulmonary arterial media, but binding to cultured cells varied between isolates. Binding in tissues and cells was inhibited by the ANG II type 1 (AT1) receptor antagonist losartan but not by the type 2 (AT2) receptor antagonist PD-123319. Microautoradiographic studies indicated that cultured PASMCs exhibit heterogeneity with regard to ANG II binding sites. Addition of ANG II to serum-deprived PASMCs, exhibiting a relatively high level of 125I-[Sar1,Ile8]ANG II binding, led to a dose-dependent stimulation of DNA synthesis at 24 h and protein synthesis at 48 h. ANG II led to an increase in cell size without an increase in cell number. These effects were inhibited by losartan but not by PD-123319. In addition, ANG II led to rapid activation of mitogen-activated protein kinase (MAPK), and ANG II-stimulated DNA synthesis was inhibited by the specific inhibitor of MAPK PD-98059. We conclude that the AT1 receptor is expressed by human PASMCs in vivo and in vitro and is coupled to activation of MAPK and increased DNA and protein synthesis in vitro. These results are consistent with the hypothesis that ANG II may be involved in human pulmonary vascular remodeling.
 ...
PMID:Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors. 1048 50

The present study aimed to investigate the molecular mechanism(s) of insulin action on angiotensinogen (ANG) secretion and gene expression in kidney proximal tubular cells exposed to high levels of glucose. Immortalized rat proximal tubular cells (IRPTC) were cultured in monolayer. The levels of rat ANG and ANG messenger RNA in the IRPTC were quantified by a specific RIA for rat ANG (RIA-rANG) and by an RT-PCR assay. Insulin inhibited the stimulatory effect of a high level of glucose (25 mM) and phorbol 12-myristate 13-acetate, an activator of protein kinase C) on the secretion of ANG and the expression of the ANG messenger RNA in IRPTC. This inhibitory action of insulin on the ANG secretion and gene expression was blocked by PD98059 (an inhibitor of mitogen-activated protein kinase kinase) but not by Wortmannin (an inhibitor of phosphatidylinositol-3-kinase). PD98059 was effective in inhibiting the phosphorylation of MEK 1/2 and p44/42 MAP kinase in IRPTC stimulated by insulin. These studies demonstrate that insulin prevents the stimulatory effect of high levels of glucose on the expression of the renal ANG gene in IRPTC, at least in part, via the MAPK kinase signal transduction pathway, subsequently inhibiting the activation of the local renal renin-angiotensin system.
 ...
PMID:Insulin inhibits angiotensinogen gene expression via the mitogen-activated protein kinase pathway in rat kidney proximal tubular cells. 1053 59

Cardiac hypertrophy is an adaptive process to an increased hemodynamic overload. When cardiomyocytes cultured on silicone dishes were stretched, second messengers such as protein kinase C (PKC), Raf-1 kinase, and mitogen-activated protein (MAP) kinases were activated, which were followed by increased protein synthesis. Moreover, pretreatment with an angiotensin II (AngII) type 1 receptor antagonist dimished an increase in protein synthesis, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. These suggest the linkage of the cardiac renin-angiotensin system to the formation of pressure-overload hypertrophy. Indeed, in the stretch-conditioned medium the levels of AngII concentration were increased. Also, mechanical stretch enhanced endothelin (ET)-1 release from the cardiomyocytes and activated the Na(+)/H(+) exchanger independently of these vasoactive peptides. In the second part, we examined AngII-induced signaling pathways both in cardiac myocytes and in cardiac fibroblasts. AngII-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts AngII activated MAP kinases through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and PKC activation was necessary in cardiac myocytes. We further explored norepinephrine (NE)-induced signaling pathways in cardiac myocytes. NE activated Raf-1 kinase and MAP kinases and increased amino acid uptake in cardiomyocytes of neonatal rats. beta-adrenoceptor (AR) stimulation as well and alpha1-AR stimulation was involved in NE-induced MAP kinase activation. It is noteworthy that unlike in other cell types not only PKC activation but also protein kinase A (PKA) activation increased the activities of Raf-1 kinase and MAP kinases in cardiac myocytes and induced cell growth. Finally, we observed that beta-AR-induced activation of MAP kinases is dependent on both Gs/cAMP/PKA and Gi/Src/Ras signaling pathways and that phosphorylation of beta-AR is critical to the cross talk between these signaling pathways.
 ...
PMID:Molecular basis of cardiac hypertrophy. 1066 10

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.
 ...
PMID:Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. 1069 53

Vascular hypertrophy occurs during chronic hypertension and contributes to the elevation of peripheral vascular resistance in hypertension. In this study, we examined whether acute pressure overloading of the vascular wall produces activation of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in isolated perfused rat aortae, and examined whether the mechanical overloading-induced MAP kinase activation is mediated via the vascular angiotensin system. Aortae were perfused with Tyrode solution. Increases in perfusion pressure caused a pressure-dependent increase in MAP kinase activity in endothelium-intact aortae and in endothelium-denuded aortae. The increase in MAP kinase activity induced by pressure loading was inhibited by the angiotensin receptor antagonist, losartan, the renin inhibitor, pepstatin A, and the angiotensin-converting enzyme inhibitor, captopril. Ca(2+) depletion and the Ca(2+) channel antagonist, nifedipine, did not affect the pressure loading-induced MAP kinase activation. The results of the present study suggest that pressure loading of the vascular wall per se can activate MAP kinases in the vasculature and that the MAP kinase activation is mediated at least partly via the vascular angiotensin system. It seems unlikely that the pressure loading-induced increase in MAP kinase activity is mainly mediated via increases in Ca(2+) influx in vascular cells.
 ...
PMID:Angiotensin II mediates pressure loading-induced mitogen-activated protein kinase activation in isolated rat aorta. 1072 70

The atherogenic effect of the renin-angiotensin system can be explained, in part, by the influence of its effector, angiotensin II (Ang II), on vascular smooth muscle cell (VSMC) growth. There is evidence that reactive oxygen species (ROS) play a role in the atherogenesis and activation of mitogen-activating protein (MAP) kinases, which are involved in proliferation and differentiation. The study was performed to further characterize the role of ROS in Ang II-mediated MAP kinase activation and the regulation of the transcription factor activator protein-1 (AP-1). Rat VSMCs were stimulated with Ang II. The activities of MAP kinases were assessed by Western blot analysis or by immunocomplex kinase assay. AP-1 binding was determined by using an electrophoretic mobility shift assay. Rat VSMCs were treated with Ang II-activated MAP kinases, extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK), p38 MAP kinase (p38 MAPK), and their downstream effector, AP-1. Interestingly, only the activation of ERK1/2, but not JNK or p38 MAPK, was tyrosine kinase, protein kinase C, and MEK1/2 dependent. Ang II also induced the rapid formation of ROS, which could be inhibited by a specific antibody as well as by antisense against the p22phox subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also solely inhibited p38 MAPK but did not affect ERK. The results indicate that in VSMCs, Ang II activates MAP kinases and AP-1 through different pathways; the results further suggest that ROS, generated by p22phox, mediate Ang II-induced JNK and p38 MAPK activation, which may contribute to the pathogenesis of atherosclerosis.
 ...
PMID:Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. 1076 57

Reducing luminal NaCl concentration in the macula densa region of the nephron stimulates renin secretion, and this response is blocked by a specific inhibitor of cyclooxygenase-2 (COX-2) (Traynor, T. R., Smart, A., Briggs, J. P., and Schnermann, J. (1999) Am. J. Physiol. Renal Physiol. 277, F706-710). To study whether low NaCl activates COX-2 activity or expression we clonally derived a macula densa cell line (MMDD1 cells) from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins. MMDD1 cells express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and showed rapid (86)Rb(+) uptake that was inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. Isosmotic exposure of MMDD1 cells to low NaCl (60 mm) caused a prompt and time-dependent stimulation of prostaglandin E(2) (PGE(2)) release that was prevented by the COX-2 specific inhibitor NS-398 (10 microm). Reducing NaCl to 60 and 6 mm for 16 h increased COX-2 expression in a chloride-dependent fashion. Low NaCl phosphorylated p38 kinase within 30 min and ERK1/2 kinases within 15 min without changing total MAP kinase levels. Low NaCl-stimulated PGE(2) release and COX-2 expression was inhibited by SB 203580 and PD 98059 (10 microm), inhibitors of p38 and ERK kinase pathways. We conclude that low chloride stimulates PGE(2) release and COX-2 expression in MMDD1 cells through activation of MAP kinases.
 ...
PMID:Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. 1098 5

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
 ...
PMID:Calcineurin blockade prevents cardiac mitogen-activated protein kinase activation and hypertrophy in renovascular hypertension. 1101 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>