Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous evidence has indicated a role for changes in cell membrane cholesterol in the modulation of [Ca2+]i responses and smooth muscle contraction to vascular agonists. However, the actions of plasma cholesterol-lowering agents such as 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (eg, simvastatin) have not been defined. Such agents may in addition affect isoprenoid intermediates that may play a role in signal transduction pathways involving G proteins. Arginine vasopressin-induced [Ca2+]i responses in A10 rat vascular myocytes were therefore studied in vitro. Vasopressin stimulated an initial peak [Ca2+]i that was independent of extracellular Ca2+ entry and a subsequent plateau that was dependent on Ca2+ influx, mainly through receptor-operated dihydropyridine-insensitive divalent cation channels. Simvastatin-treated A10 cells (5 mg/L for 24 hours) showed a normal initial peak response to vasopressin, but the plateau phase of Ca2+ entry was significantly impaired. By use of Mn2+ quenching of intracellular fura 2 to measure divalent cation entry, the maximal rate of vasopressin-stimulated Mn2+ entry was impaired in simvastatin-treated cells by 52%. Mevalonate (1 mmol/L for 4 hours at 37 degrees C) reversed all the changes in simvastatin-treated cells. There were no associated changes in total cellular cholesterol or fluorescence anisotropy measurements with simvastatin treatment. Measurements of inositol-1,4,5-trisphosphate mass showed that simvastatin did not impair the initial peak response to vasopressin but significantly reduced the subsequent plateau phase. These changes were also reversed with mevalonate incubation. These findings suggest that simvastatin has additional effects on [Ca2+]i homeostasis that are independent of changes in total cell cholesterol.
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PMID:3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibition modulates vasopressin-stimulated Ca2+ responses in rat A10 vascular smooth muscle cells. 829 56

Simvastatin (SV), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity inhibits migration and proliferation of vascular smooth muscle cells (SMC). To investigate whether these effects of SV are related to inhibition of cell calcium mobilization, cultured SMC obtained from rat aorta were loaded with Fura-2 to determine the basal cytosolic free calcium levels ([Ca2+]i) and the agonist-stimulated Ca2+ mobilization. SV (20 mu M) transiently increased cytosolic free calcium, an effect that depends mainly on intracellular calcium release (68%). This effect of SV was markedly reduced (75%) by thapsigargin, an inhibitor of the Ca2+ ATPase of inositol 1,4,5-triphosphate (InsP3)-sensitive calcium pools. Incubation of cells with SV (15 min) inhibited the mobilization of Ca2+ by angiotensin II, platelet-derived growth factor, and vasopressin (IC50 = 5 mu M). SV did not affect inositol trisphosphate (InsP3) levels or modify its generation by angiotensin II (Ang II) and vasopressin. Furthermore, in saponin-permeabilized cells, SV abolished the release of calcium by 2,3-dideoxy-InsP3. SV reduced the effect of thapsigargin on InsP3-sensitive stores by 67%, suggesting that SV depletes these calcium pools. The inhibitory effect of SV on calcium mobilization was prevented by coincubation of cultured cells (24 h) with 1 mM mevalonic acid, the product of HMG-CoA reductase activity. These results support the notion that SV inhibits [corrected] the migration and proliferation of SMC by directly affecting cell Ca2+.
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PMID:Simvastatin releases Ca2+ from a thapsigargin-sensitive pool and inhibits InsP3-dependent Ca2+ mobilization in vascular smooth muscle cells. 890

Arginine vasopressin (AVP) has been shown to directly induce neonatal rat cardiac fibroblasts (CFs) proliferation, a major component involved in cardiac hypertrophy. Herein, we explored whether AVP is also a growth factor for adult rat CFs and, if so, whether the growth effect could be inhibited by simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. AVP significantly increased DNA synthesis in adult rat CFs by 73.5 +/- 5.1% (P < or = 0.05), an effect inhibited by V1 receptor antagonist, d(CH(2))(5)[Tyr(2)(Me), Arg(8)]-vasopressin. AVP also activated extracellular signal-regulated kinase 1/2 (ERK1/2) as assessed by MBP phosphotransferase activity (5.1 +/- 0.6 fold over basal level, P < or = 0.05) and Western blot analysis, and effects were mimicked by protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but abolished by inhibiting cellular PKC through chronic PMA incubation. In addition, AVP induced PKC activation (27.2 +/- 3.8% from a basal value of 9.3 +/- 0.7%, P < or = 0.05). AVP-induced increase in DNA synthesis could be attenuated by the specific inhibitors of ERK1/2 (PD98059), PI3K (LY294002), and AKT (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, HIMO). Simvastatin inhibited the effects of AVP on DNA synthesis, ERK1/2, and PKC activation in a dose-dependent manner. Phosphatidylinositol-3-kinase (PI3K)-dependent AKT activation induced by AVP was also inhibited by simvastatin. The effects of simvastatin on ERK1/2, PKC, and AKT activation and DNA synthesis could be reversed by mevalonate. These results support a growth-inducing effect of AVP on adult rat CFs through ERK and AKT signalings and the growth effect could be attenuated by simvastatin via inhibiting these two pathways.
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PMID:Involvement of ERK and AKT signaling in the growth effect of arginine vasopressin on adult rat cardiac fibroblast and the modulation by simvastatin. 1858 Dec 3

Statins are 3-hydroxyl-3-methyglutaryl-CoA reductase inhibitors that are commonly used to inhibit cholesterol biosynthesis. Emerging data have suggested that they also have "pleotropic effects," including modulating actin cytoskeleton reorganization. Here, we report an effect of simvastatin on the trafficking of aquaporin-2 (AQP2). Specifically, simvastatin induced the membrane accumulation of AQP2 in cell cultures and kidneys in situ. The effect of simvastatin was independent of protein kinase A activation and phosphorylation at AQP2-Ser(256), a critical event involved in vasopressin (VP)-regulated AQP2 trafficking. Further investigation showed that simvastatin inhibited endocytosis in parallel with downregulation of RhoA activity. Overexpression of active RhoA attenuated simvastatin's effect, suggesting the involvement of this small GTPase in simvastatin-mediated AQP2 trafficking. Finally, the effect of simvastatin on urinary concentration was investigated in VP-deficient Brattleboro rats. Simvastatin acutely (3-6 h) increased urinary concentration and decreased urine output in these animals. In summary, simvastatin regulates AQP2 trafficking in vitro and urinary concentration in vivo via events involving downregulation of Rho GTPase activity and inhibition of endocytosis. Our study provides an alternative mechanism to regulate AQP2 trafficking, bypassing the VP-vasopressin receptor signaling pathway.
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PMID:Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. 2156 96