Background: while Ca2+ signaling plays a crucial role in regulating inflammatory response, the role plays by Ca2+ mobilization from intracellular stores remains unclear. SERCAs are pumps that control intracellular calcium (Ca2+) storage and we have, recently, established that full platelet activation requires SERCA3, indicating a specific role for this pump. And SERCA3 is expressed in leukocytes, platelets and endothelial cells, which actively participate to inflammation.
Aims: Is SERCA3 important in two major inflammatory processes, endothelial hyperpermeability and leukocytes activation?
Methods: Wild-type (WT) and SERCA3 knockout (SERCA3-/-) mice were compared, lung vascular endothelial cells (mLECs) isolated from these animals and Human pulmonary artery endothelial cells (hPAEC). Different inflammation models were explored in mice and thrombin challenging was analysed in primary endothelial cells. Leukocytes behavior was explored in vivo using intravital microscopy for rolling/adhesion and myeloperoxidase assay for leukocytes recruitment. In vitro hyperpermeability and cytoskeletal reorganization of human and murin lung endothelial cells were investigated using transendothelial electrical resistance and actin/VE-cadherin immunostaining, respectively.
Results: In SERCA3-/-, early leukocyte mobilization in response to FeCl3 injury was abolished independently of platelet activation, as similar results were observed in thrombocytopenia induced animals. Leukocyte rolling velocity and adhesion were also significantly reduced after LPS challenging. In Arthus inflammation model, an altered leukocyte recruitment was observed in platelet dependent way. Moreover, absence of platelets uncovered that lack of SERCA3 prevented inflammation-induced haemorrhage suggesting a role for endothelium.
SERCA3-/- mLECs studies showed that Ca2+ release and stress fiber formation in response to low concentration of thrombin were abolished. In thrombin-stimulated hPAEC, pharmacological inhibition of SERCA3, was also associated to reduced Ca2+ release, stress fiber formation, VE-cadherin disassembly and barrier disruption.
Conclusions: Our results suggest that lack of SERCA3-dependent Ca2+ release is associated to lower endothelial barrier disruption and weaker inflammatory responses.
To cite this abstract in AMA style:Beddek K, Adam F, Saller F, Borgel D, Denis C, Bobe R. Ca2+ Release from Stores Controlled by Sarco/Endoplamic Reticulum Ca2+-ATPase 3 (SERCA3) Is Involved in Endothelial Permeability and Inflammatory Response [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/ca2-release-from-stores-controlled-by-sarco-endoplamic-reticulum-ca2-atpase-3-serca3-is-involved-in-endothelial-permeability-and-inflammatory-response/. Accessed November 26, 2020.
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