STIM2 (Stromal Interaction Molecule 2)–Mediated Increase in Resting Cytosolic Free Ca 2+ Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension
| Autor: | Marisela Rodriguez, Angela Balistrieri, Ayako Makino, Kimberly M. McDermott, Jian Wang, Shanshan Song, Jason X.-J. Yuan, Aleksandra Babicheva, Shane G. Carr, Ramon J. Ayon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
biology Chemistry NFAT 030204 cardiovascular system & hematology CREB Sarcoplasmic reticulum membrane Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Downregulation and upregulation Hypoxic pulmonary vasoconstriction Internal Medicine STAT protein biology.protein Signal transduction Protein kinase B |
| Zdroj: | Hypertension. 71:518-529 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.117.10503 |
| Popis: | An increase in cytosolic free 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 (stromal interaction molecule 2), a Ca 2+ sensor in the sarcoplasmic reticulum 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 , whereas 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 (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 2+ ] 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 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. |
| Databáze: | OpenAIRE |
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