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• W2950842070 abstract "Abstract We present a biochemical model of the wall shear stress (WSS)-induced activation of endothelial nitric oxide synthase (eNOS) in an endothelial cell (EC). The model includes three key mechanotransducers: mechanosensing ion channels, integrins and G-protein-coupled receptors. The reaction cascade consists of two interconnected parts. The first is rapid activation of calcium, which results in formation of calcium-calmodulin complexes, followed by recruitment of eNOS from caveolae. The second is phosphoryaltion of eNOS by protein kinases PKC and AKT. The model also includes a negative feedback loop due to inhibition of calcium influx into the cell by cyclic guanosine monophosphate (cGMP). In this feedback, increased nitric oxide (NO) levels cause an increase in cGMP levels, so that cGMP inhibition of calcium influx can limit NO production. The model was used to predict the dynamics of NO production by an EC subjected to a step increase of WSS from zero to a finite physiologically relevant value. Among several experimentally observed features, the model predicts a highly nonlinear, bipha-sic transient behavior of eNOS activation and NO production: a rapid initial activation due to the very rapid influx of calcium into the cytosol (occurring within 1 to 5 minutes) is followed by a sustained period of activation due to protein kinases. Acronyms AKT, protein kinase B; [Ca 2+ ] c , [Ca 2+ ] s , [Ca 2+ ] e and [Ca 2+ ] b , cytosolic, stored, external and buffer concentrations of calcium ions, respectively; Ca 3 -CaM and Ca 4 -CaM, calcium-calmodulin complexes with 3 and 4 calcium ions bound to CaM, respectively; CaM, calmodulin; CCE, capacitative calcium entry; cGMP, cyclic guanosine monophosphate; EC, endothelial cell; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; eNOS cav , eNOS bound to caveolin; eNOS*, eNOS-CaM complex phosphorylated at Ser-1197; eNOS 0 , caveolin-bound eNOS phosphorylated at Thr-495; ER, endoplasmic reticulum; FAK, focal adhesion kinase; G, active G proteins; G t , total G proteins; GPCR, G-protein-coupled receptors; Hsp90, heat shock protein 90; GTP, guanosine triphosphate; IP 3 , inositol triphosphate; L-Arg, L-form of arginine; MSIC, mechanosensing ion channel; NO, nitric oxide; O 2 , oxygen; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PIP 3 , phos-phatidylinositol (3,4,5)-triphosphate; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; RBC, red blood cell; sGC, soluble guanylate cyclase; WSS, wall shear stress" @default.
• W2950842070 created "2019-06-27" @default.
• W2950842070 creator A5004264767 @default.
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• W2950842070 date "2016-05-05" @default.
• W2950842070 modified "2023-10-17" @default.
• W2950842070 title "Shear-induced nitric oxide production by endothelial cells" @default.
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• W2950842070 doi "https://doi.org/10.1101/051946" @default.
• W2950842070 hasPublicationYear "2016" @default.
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