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• W2149309105 abstract "Platelets are activated by increased cytosolic Ca2+ concentration ([Ca2+]i) following store-operated calcium entry (SOCE) accomplished by calcium-release-activated calcium (CRAC) channel moiety Orai1 and its regulator STIM1. In other cells, Ca2+ transport is regulated by 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 formation is inhibited by klotho and excessive in klotho-deficient mice (kl/kl). The present study explored the effect of klotho deficiency on platelet Ca2+ signaling and activation. Platelets and megakaryocytes isolated from WT and kl/kl-mice were analyzed by RT-PCR, Western blotting, confocal microscopy, Fura-2-fluorescence, patch clamp, flow cytometry, aggregometry, and flow chamber. STIM1/Orai1 transcript and protein levels, SOCE, agonist-induced [Ca2+]i increase, activation-dependent degranulation, integrin αIIbβ3 activation and aggregation, and thrombus formation were significantly blunted in kl/kl platelets (by 27–90%). STIM1/Orai1 transcript and protein levels, as well as CRAC currents, were significantly reduced in kl/kl megakaryocytes (by 38–73%) and 1,25(OH)2D3-treated WT megakaryocytes. Nuclear NF-κB subunit p50/p65 abundance was significantly reduced in kl/kl-megakaryocytes (by 51–76%). Transfection with p50/p65 significantly increased STIM1/Orai1 transcript and protein levels in megakaryocytic MEG-01 cells (by 46–97%). Low-vitamin D diet (LVD) of kl/kl mice normalized plasma 1,25(OH)2D3 concentration and function of platelets and megakaryocytes. Klotho deficiency inhibits platelet Ca2+ signaling and activation, an effect at least partially due to 1,25(OH)2D3-dependent down-regulation of NF-κB activity and STIM1/Orai1 expression in megakaryocytes.—Borst, O., Münzer, P., Schmid, E., Schmidt, E.-M., Russo, A., Walker, B., Yang, W., Leibrock, C., Szteyn, K., Schmidt, S., Elvers, M., Faggio, C., Shumilina, E., Kuro-o, M., Gawaz, M., Lang, F. 1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice. FASEB J. 28, 2108–2119 (2014). www.fasebj.org" @default.
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• W2149309105 date "2014-02-12" @default.
• W2149309105 modified "2023-10-14" @default.
• W2149309105 title "1,25(OH) ₂ vitamin D ₃ ‐dependent inhibition of platelet Ca ²⁺ signaling and thrombus formation in klotho‐deficient mice" @default.
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• W2149309105 doi "https://doi.org/10.1096/fj.13-239277" @default.
• W2149309105 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24522202" @default.
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