STIM2 (Stromal Interaction Molecule 2)-Mediated Increase in Resting Cytosolic Free Ca Concentration Stimulates PASMC Proliferation in Pulmonary Arterial Hypertension.
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
Hypertension (Dallas, Tex. : 1979)
An increase in cytosolic free Ca concentration ([Ca]) 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] 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], whereas overexpression of STIM2 in normal PASMCs increases the resting [Ca] The increased resting [Ca] 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] 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], 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] 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.
Carboxyl terminus of Hsc70-interacting protein (CHIP) promotes pulmonary artery smooth muscle cell (PASMC) proliferation enhancement of intracellular Ca concentration ([Ca]).
Dong Fang,Zhang Jun
Experimental lung research
AIMS OF THE STUDY:To investigate the effect of carboxyl terminus of Hsc70-interacting protein (CHIP) on pulmonary arterial smooth muscle cell (PASMC) proliferation and the underlying mechanism. PASMCs were harvested from distal PAs isolated from SD rat lungs and cultured. After CHIP overexpression, PASMCs were exposed to normoxia or hypoxia for 60 h. Then, PASMC proliferation, store-operated Ca entry (SOCE), [Ca] and the expression of TRPC1, TRPC4, and TRPC6 in PASMCs were measured. CHIP overexpression promoted PASMC proliferation, SOCE, [Ca] and the expression of TRPC1, TRPC4, and TRPC6. CHIP stimulates PASMC proliferation likely by targeting the TRPC1,4,6-SOCE-[Ca] signaling pathway.