Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A close interaction between adrenergic nerves and angiotensin systems has been documented. The present study was designed to investigate the mechanisms of angiotensin-receptor blocker (ARB) suppression of beta-adrenergic receptor stimulation-induced cardiac hypertrophy. Chronic isoproterenol (ISO)-induced cardiac hypertrophy was inhibited in wild-type mice and AT1aR(-/-) mice treated with the ARB Candesartan (CV11974). Acute ISO-induced increase in phosphorylation levels of ERK MAPK was completely inhibited and increases in phosphorylation levels of p38 and JNK MAPKs were partially suppressed in both types of mice. Analysis of the activity of the small GTPase-regulating protein Raf indicated that the mechanisms by which ARB inhibits the Raf/MEK/ERK pathway under beta-adrenergic receptor stimulation basically depended on changes in the binding activities of Ras (stimulatory to Raf cascade) and Rap-1 (inhibitory to Raf cascade). Binding activities of Ras and Rap-1 in the heart were markedly augmented by ISO, whereas ARB suppressed only Ras, but not Rap-1, binding activity. Raf immunoprecipitation results confirmed that ISO-induced increases in its association with total and phosphorylated forms of MEK were completely normalized by ARB. These results might provide a molecular basis for the beneficial effects of AT1-receptor antagonists on cardiac remodeling and functions in patients with sympatho-excitatory heart failure.
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PMID:Effects of angiotensin type I receptor blockade on the cardiac Raf/MEK/ERK cascade activated via adrenergic receptors. 2056 18

We tested the hypothesis that AT1R blockade modulates the shear stress-induced (SS) synthesis of nitric oxide (NO) in endothelial cells (EC). The AT1R blocker Candesartan in the absence of the ligand angiotensin II (ang II) potentiated SS-induced NO synthesis accompanied by increased p-eNOS(Ser1177) and decreased p-eNOS(Thr495). Candesartan also inhibited SS-induced ERK activation and increased intracellular calcium transient in a time-dependent manner. To confirm the role of ERK to modulate p-eNOS(Thr495) and calcium to modulate p-eNOS(Ser1177), the MEK inhibitor U0126 and the calcium chelator BAPTA-AM were used, respectively. Pre-treatment of EC with U0126 completed abrogated basal and SS-induced ERK activation, inhibited p-eNOS(Thr495) and increased NO production by SS. On the other hand, pre-treatment of EC with BAPTA-AM decreased the effects of SS alone or in combination with Candesartan to induce p-eNOS(Ser1177) and partially inhibited the effects of Candesartan to potentiate NO release by SS. The AT1R blockers Losartan and Telmisartan were also tested but only Telmisartan potentiated NO synthesis and blocked SS-induced AT1R activation. Altogether, we provide evidence that Candesartan and Telmisartan potentiate SS-induced NO production even in the absence of the ligand ang II. This response requires both the inhibition of eNOS phosphorylation at its inhibitory residue Thr(495) as well as the increase of eNOS phosphorylation at its excitatory residue Ser(1177). In addition, the response is associated with inhibition of SS-induced ERK activation as well as increasing intracellular calcium transient. One may speculate that these yet undescribed events may contribute to the benefits of ARBs in cardiovascular diseases.
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PMID:AT1 receptor blocker potentiates shear-stress induced nitric oxide production via modulation of eNOS phosphorylation of residues Thr(495) and Ser(1177.). 2421 Dec 12

Objective To investigate the effect of candesartan on angiotensin II (Ang II)-induced proliferation and migration of vascular smooth muscle cells and its effect on connexin 43 (Cx43). Methods A7r5 cells were cultured in vitro and randomly divided into control group, AngII group and AngII combined with candesartan group. Cell viability was detected by CCK-8 assay; the migration and invasion ability of A7r5 cells were measured by wound-healing and TranswellTM assay; the expression and distribution of Cx43 on A7r5 cells were detected by immunofluorescence assay. Cx43, osteopontin (OPN), proliferating cell nuclear antigen (PCNA), p-MEK1/2 and p-ERK1/2 protein levels of A7r5 cells were detected by Western blot analysis. Results Compared with the control group, the AngII group had higher cell proliferation and migration ability, and the AngII combined with candesartan group had a lower concentration than the AngII group. Cx43 was expressed in the A7r5 cell membrane and nuclear membrane. The expression of Cx43 were enhanced in the AngII group than in the control group, and the expressions of Cx43, OPN, PCNA, p-MEK1/2 and p-ERK1/2 significantly increased compared with AngII. The expression of protein significantly decreased in AngII combined with candesartan group. Conclusion Candesartan can reduce the proliferation and migration of smooth muscle cells induced by AngII, and its mechanism may be related to Cx43 and MEK/ERK signaling pathways.
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PMID:[Candesartan inhibits the angiotensin II-induced proliferation and migration of rat thoracic aortic smooth muscle A7r5 cells and its mechanism]. 3097 79