1,25(OH) 2 vitamin D 3 ‐dependent inhibition of platelet Ca 2+ signaling and thrombus formation in klotho‐deficient mice

• DOI: 10.1096/fj.13-239277
• Publication Date: 2014-02-13T06:02:50Z
• Authors: Oliver Borst; Patrick Münzer; Evi Schmid; Eva‐Maria Schmidt; Antonella Russo; Britta Walker; Wenting Yang; Christina Leibrock; Kalina Szteyn; Sebastian Schmidt; Margitta Elvers; Caterina Faggio; Ekaterina Shumilina; Makoto Kuro‐o; Meinrad Gawaz; Florian Lang
• Keywords: Orai1; Klotho

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