Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P10415 (
Bcl-2
)
33,771
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca
2+
Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension. 2935 61
