STIM2 (Stromal Interaction Molecule 2)–mediated increase in resting cytosolic free Ca2+ concentration stimulates PASMC proliferation in pulmonary arterial hypertension

Shanshan Song, Shane G. Carr, Kimberly McDermott, Marisela Rodriguez, Aleksandra Babicheva, Angela Balistrieri, Ramon J. Ayon, Jian Wang, Ayako Makino, Jason Yuan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)518-529
Number of pages12
JournalHypertension
Volume71
Issue number3
DOIs
StatePublished - Jan 1 2018

Fingerprint

Pulmonary Hypertension
Pulmonary Artery
Smooth Muscle Myocytes
Cell Proliferation
NFATC Transcription Factors
STAT3 Transcription Factor
Apoptosis
Stromal Interaction Molecule 2
Vasoconstriction
Lung
Down-Regulation
Proteins
Sarcoplasmic Reticulum
Small Interfering RNA
Blood Vessels
Up-Regulation
Phosphorylation

Keywords

  • Ca2+ signaling
  • Cell apoptosis
  • Cell proliferation
  • Pulmonary arterial hypertension
  • Sore-operated Ca2+ entry

ASJC Scopus subject areas

  • Internal Medicine

Cite this

STIM2 (Stromal Interaction Molecule 2)–mediated increase in resting cytosolic free Ca2+ concentration stimulates PASMC proliferation in pulmonary arterial hypertension. / Song, Shanshan; Carr, Shane G.; McDermott, Kimberly; Rodriguez, Marisela; Babicheva, Aleksandra; Balistrieri, Angela; Ayon, Ramon J.; Wang, Jian; Makino, Ayako; Yuan, Jason.

In: Hypertension, Vol. 71, No. 3, 01.01.2018, p. 518-529.

Research output: Contribution to journalArticle

Song, Shanshan ; Carr, Shane G. ; McDermott, Kimberly ; Rodriguez, Marisela ; Babicheva, Aleksandra ; Balistrieri, Angela ; Ayon, Ramon J. ; Wang, Jian ; Makino, Ayako ; Yuan, Jason. / STIM2 (Stromal Interaction Molecule 2)–mediated increase in resting cytosolic free Ca2+ concentration stimulates PASMC proliferation in pulmonary arterial hypertension. In: Hypertension. 2018 ; Vol. 71, No. 3. pp. 518-529.
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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.",
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AU - Carr, Shane G.

AU - McDermott, Kimberly

AU - Rodriguez, Marisela

AU - Babicheva, Aleksandra

AU - Balistrieri, Angela

AU - Ayon, Ramon J.

AU - Wang, Jian

AU - Makino, Ayako

AU - Yuan, Jason

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N2 - 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.

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