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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 71; no. 3; pp. 518 - 529
• Main Authors: Song, Shanshan, Carr, Shane G, McDermott, Kimberly M, Rodriguez, Marisela, Babicheva, Aleksandra, Balistrieri, Angela, Ayon, Ramon J, Wang, Jian, Makino, Ayako, Yuan, Jason X.-J
• Format: Journal Article
• Language: English
• Published: American Heart Association, Inc 01-03-2018
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.117.10503

An increase in cytosolic free Ca concentration ([Ca]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 Ca sensor in the sarcoplasmic reticulum membrane, is required for raising the resting [Ca]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]cyt, whereas overexpression of STIM2 in normal PASMCs increases the resting [Ca]cyt. The increased resting [Ca]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 [Ca]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 [Ca]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]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.