STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca

An increase in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation leading to vascular wall thickening. Here, we report that STIM2, a Ca(2+) sensor in the sarcoplasmic reticulum (SR) membrane, is required for raising the resting [Ca(2+)](cyt) in PASMCs from patients with pulmonary arterial hypertension (PAH) and activating signaling cascades that stimulate PASMC proliferation and inhibit PASMC apoptosis. Downregulation of STIM2 in PAH-PASMCs reduces the resting [Ca(2+)](cyt), while overexpression of STIM2 in normal PASMCs increases the resting [Ca(2+)](cyt). The increased resting [Ca(2+)](cyt) in PAH-PASMCs is associated with enhanced phosphorylation (p) of CREB, STAT3 and AKT, increased NFAT nuclear translocation, and elevated level of Ki67 (a marker of cell proliferation). Furthermore, the STIM2-associated increase in the resting [Ca(2+)](cyt) also upregulates the anti-apoptotic protein Bcl-2 in PAH-PASMCs. Downregulation of STIM2 in PAH-PASMCs with siRNA a) decreases the level of pCREB, pSTAT3 and pAKT and inhibits NFAT nuclear translocation, thereby attenuating proliferation, and b) decreases Bcl-2, which leads to an increase of apoptosis. In summary, these data indicate that upregulated STIM2 in PAH-PASMCs, by raising the resting [Ca(2+)](cyt), contributes to enhancing PASMC proliferation by activating the CREB, STAT3, AKT and NFAT signaling pathways and stimulating PASMC proliferation. The STIM2-associated increase in the resting [Ca(2+)](cyt) is also involved in upregulating Bcl-2 that makes PAH-PASMCs resistant to apoptosis, and thus plays an important role in sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in patients with PAH.