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- Title
1,25(OH)<sub>2</sub> vitamin D<sub>3</sub>-dependent inhibition of platelet Ca<sup>2+</sup> signaling and thrombus formation in klotho-deficient mice.
- Authors
Borst, Oliver; Münzer, Patrick; Schmid, Evi; Schmidt, Eva-Maria; Russo, Antonella; Walker, Britta; Wenting Yang; Leibrock, Christina; Szteyn, Kalina; Schmidt, Sebastian; Elvers, Margitta; Faggio, Caterina; Shumilina, Ekaterina; Kuro-o., Makoto; Gawaz, Meinrad; Lang, Florian
- Abstract
Platelets are activated by increased cytsolic Ca2+ concentration ([Ca2+]i) following store-operated calcium entry (SOCE) accomplished by calcium release-activated calcium (CRAC) channel moiety Orail 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 prese study explored the effect of klotho deficiency o platelet Ca2+ signaling and activation. Platelets an megakaryocytes isolated from WT and kl/kl-mice we analyzed by RT-PCR, Western blotting, confocal microscopy, Fura-2-fluorescence, patch clamp, flow cytometry, aggregometry, and flow chamber. STIM1/Orail transcript and protein levels, SOCE, agonist-induce [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/Orail transcript and protein levels, as well as CRAC currents, were significantly reduced in kl/kl megakaryocytes (by 38-73%) 1,25(OH)2D3-treated WT megakaryocytes. Nuclear NF-ΚB subunit p50/p65 abundance was significant reduced in kl/kl-megakaryocytes (by 51-76%). Transfection with p50/p65 significantly increased STIM1 Orall 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 megakaryocyte. 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/Orail expression in megakaryocytes.
- Subjects
BLOOD platelets; MEGAKARYOCYTES; PHYSIOLOGICAL effects of calcium; PROTEIN analysis; GENETIC transcription regulation
- Publication
FASEB Journal, 2014, Vol 28, Issue 5, p2108
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-239277