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STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca2+ Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension.


ABSTRACT: An increase in cytosolic free Ca2+ concentration ([Ca2+]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 (stromal interaction molecule 2), a Ca2+ sensor in the sarcoplasmic reticulum membrane, is required for raising the resting [Ca2+]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 [Ca2+]cyt, whereas overexpression of STIM2 in normal PASMCs increases the resting [Ca2+]cyt The increased resting [Ca2+]cyt in PAH-PASMCs is associated with enhanced phosphorylation (p) of CREB (cAMP response element-binding protein), STAT3 (signal transducer and activator of transcription 3), and AKT, increased NFAT (nuclear factor of activated T-cell) nuclear translocation, and elevated level of Ki67 (a marker of cell proliferation). Furthermore, the STIM2-associated increase in the resting [Ca2+]cyt also upregulates the antiapoptotic protein Bcl-2 in PAH-PASMCs. Downregulation of STIM2 in PAH-PASMCs with siRNA (1) decreases the level of pCREB, pSTAT3, and pAKT and inhibits NFAT nuclear translocation, thereby attenuating proliferation, and (2) 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 [Ca2+]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 [Ca2+]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.

SUBMITTER: Song S 

PROVIDER: S-EPMC5955710 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca<sup>2+</sup> Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension.

Song Shanshan S   Carr Shane G SG   McDermott Kimberly M KM   Rodriguez Marisela M   Babicheva Aleksandra A   Balistrieri Angela A   Ayon Ramon J RJ   Wang Jian J   Makino Ayako A   Yuan Jason X-J JX  

Hypertension (Dallas, Tex. : 1979) 20180122 3


An increase in cytosolic free Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>cyt</sub>) in pulmonary artery smooth muscle cells (PASMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation leading to vascular wall thickening. Here, we report that STIM2 (stromal interaction molecule 2), a Ca<sup>2+</sup> sensor in the sarcoplasmic reticulum membrane, is required for raising the resting [Ca<sup>2+</sup>]<sub>cyt</sub> in PASMCs from patients with pulmonary arterial hyperte  ...[more]

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