Aim: 

Vascular smooth muscle cell (VSMC) proliferation contributes to vascular restenosis, atherosclerosis and hypertension. Salicylate, the main aspirin metabolite, and other non-steroideal anti-inflammatory drugs (NSAIDs) prevent VSMC proliferation and may improve these conditions but the mechanism remains unknown. Here we asked whether salicylate and other NSAIDs may impact on cell proliferation acting on mitochondrial control of store operated Ca²⁺ entry (SOCE), a pathway involved in cell proliferation.

Methods: 

We have studied the effects of salicylate and other NSAIDs on mitochondrial potential and intracellular Ca²⁺ using fluorescence microscopy in rat A10 VSMC. Effects on cell proliferation were assessed by cell counting and expression of Stim1 and Orai1 was tested by immunocytochemistry.

Results: 

We found that A10 cells show a strong SOCE regulated by mitochondrial Ca²⁺ uptake and prevented by classic SOCE blockers such as La³⁺, 2APB and BTP2. A10 cells expressed both Orai1 and Stim1, the recently discovered proteins involved in SOCE in T cells. Salicylate and other NSAIDs prevented both SOCE and cell proliferation, at the same therapeutic concentrations. Salicylate also prevented Ca²⁺ entry induced by vasopresin. Finally, salicylate and other NSAIDs depolarize mitochondria, thus preventing mitochondrial Ca²⁺ uptake.

Conclusions: 

These results indicate that salicylate and other NSAIDs depolarize mitochondria and inhibit mitochondrial Ca²⁺ uptake, thus preventing SOCE and cell proliferation. This mechanism may contribute to explain the regulatory effects of aspirin and other NSAIDs in proliferative diseases of the vascular wall.

This work was funded by Junta de Castilla y León (SAN191/VA1806) and Ministerio de Educación y Ciencia (BFU2006-05202/BFI).