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Query: UMLS:C0020538 (
hypertension
)
170,190
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.
Hypertension
2018 03
PMID:STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca
2+
Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension. 2935 61
The increase in cytosolic Ca
2+
concentration ([Ca
2+
]
cyt
) and upregulation of calcium-sensing receptor (CaSR) and
stromal interaction molecule 2
(
STIM2
) along with inhibition of voltage-gated K
+
(K
V
) channels in pulmonary arterial smooth muscle cells (PASMC) have been implicated in the development of pulmonary arterial
hypertension
; however, the precise upstream mechanisms remain elusive. Activation of CaSR, a G protein-coupled receptor (GPCR), results in Ca
2+
release from the endoplasmic/sarcoplasmic reticulum (ER/SR) and Ca
2+
influx through receptor-operated and store-operated Ca
2+
channels (SOC). Upon Ca
2+
depletion from the SR, STIM forms clusters to mediate store-operated Ca
2+
entry. Activity of K
V
channels, like KCNA5/K
V
1.5 and KCNA2/K
V
1.2, contributes to regulating membrane potential, and inhibition of K
V
channels results in membrane depolarization that increases [Ca
2+
]
cyt
by opening voltage-dependent Ca
2+
channels. In this study, we show that activation of Notch by its ligand Jag-1 promotes the clustering of
STIM2
, and clustered
STIM2
subsequently enhances the CaSR-induced Ca
2+
influx through SOC channels. Extracellular Ca
2+
-mediated activation of CaSR increases [Ca
2+
]
cyt
in
CASR
-transfected HEK293 cells. Treatment of
CASR
-transfected cells with Jag-1 further enhances CaSR-mediated increase in [Ca
2+
]
cyt
. Moreover, CaSR-mediated increase in [Ca
2+
]
cyt
was significantly augmented in cells co-transfected with
CASR
and
STIM2
. CaSR activation results in
STIM2
clustering in
CASR/
STIM2
-cotransfected cells. Notch activation also induces significant clustering of
STIM2
. Furthermore, activation of Notch attenuates whole cell K
+
currents in
KCNA5
- and
KCNA2
-transfected cells. Together, these results suggest that Notch activation enhances CaSR-mediated increases in [Ca
2+
]
cyt
by enhancing store-operated Ca
2+
entry and inhibits KCNA5/K
V
1.5 and KCNA2/K
V
1.2, ultimately leading to voltage-activated Ca
2+
entry.
...
PMID:Notch enhances Ca
2+
entry by activating calcium-sensing receptors and inhibiting voltage-gated K
+
channels. 3218 32
