Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis.

Abstract

BACKGROUND:

Stromal interaction molecule 1 (STIM1) was recently identified as a critical component of store-operated calcium entry (SOCE) in platelets. We previously reported the Ca(2+) -sensing guanine nucleotide exchange factor CalDAG-GEFI as a critical molecule in Ca(2+) signaling in platelets.

OBJECTIVE:

To evaluate the contribution of STIM1/SOCE to Ca(2+) -dependent platelet activation and thrombosis, we here compared the activation responses of platelets lacking STIM1 and platelets lacking CalDAG-GEFI.

METHODS:

The murine Stim1 gene was conditionally deleted in the megakaryocyte/platelet lineage. CalDAG-GEFI(-/-) and Stim1(fl/fl) PF4-Cre mice, along with littermate control mice, were used for in vitro and in vivo experiments under flow as well as static conditions.

RESULTS:

Integrin α(IIb) β(3) -mediated aggregation was markedly impaired in CalDAG-GEFI-deficient but not STIM1-deficient platelets, under both static and flow conditions. In contrast, deficiency in either STIM1 or CalDAG-GEFI significantly impaired the ability of platelets to express phosphatidylserine on the cell surface. When subjected to a laser injury thrombosis model, mice lacking STIM1 in platelets were characterized by the formation of unstable platelet-rich thrombi and delayed and reduced fibrin generation in injured arterioles. In CalDAG-GEFI(-/-) mice, fibrin generation was also delayed and reduced, but platelet accumulation was almost abolished.

CONCLUSIONS:

Our studies suggest that: (i) STIM1/SOCE is critical for the procoagulant activity but not the proadhesive function of platelets; and (ii) at the site of vascular injury, STIM1 and CalDAG-GEFI are critical for the first wave of thrombin generation mediated by procoagulant platelets.

• Authors: F Ahmad, Y Boulaftali, T K Greene, T D Ouellette, M Poncz, S Feske, W Bergmeier
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 9 Issue 10 Pg. 2077-86 (Oct 2011) ISSN: 1538-7836 [Electronic] England
• PMID: 21848641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 International Society on Thrombosis and Haemostasis.

Chemical References

• Calcium Channels
• Guanine Nucleotide Exchange Factors
• Membrane Glycoproteins
• Rasgrp2 protein, mouse
• Stim1 protein, mouse
• Stromal Interaction Molecule 1
• Calcium

Topics

• Animals
• Blotting, Western
• Calcium (metabolism)
• Calcium Channels
• Guanine Nucleotide Exchange Factors (physiology)
• Male
• Membrane Glycoproteins (physiology)
• Mice
• Platelet Activation
• Stromal Interaction Molecule 1
• Thrombosis (physiopathology)