STIM2 Contributes to the Proliferative Characteristics via Increasing Basal [Ca2+]cyt in Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension

Abstract

In pulmonary arterial hypertension (PAH), excessive cell proliferation is a key mechanism that results in an obstructive vasculopathy. An increase in basal intracellular free Ca2+ concentration ([Ca2+]cyt) has been described in pulmonary artery smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH) and explains the PASMCs proliferation. STIM2 is reported to be a feedback regulator that stabilizes basal [Ca2+]cyt. A selective up‐regulation of STIM2 has been observed in PASMCs from patients with IPAH and contributes to the transition of PASMCs from a contractile phenotype to proliferative phenotype in rats. The exact mechanism of STIM2‐mediated PASMC proliferation in PAH remains unclear. We hypothesized that the augmentation in cell proliferation can be explained in part by a STIM2‐mediated increase in basal [Ca2+]cyt. Compared with normal PASMCs, IPAH PASMCs had increased STIM2 expression and basal [Ca2+]cyt. Overexpression of STIM2 in normal PASMCs increased basal [Ca2+]cyt, phosphorylated‐Akt and mTOR levels, and enhanced the activation of CREB, STAT3 and NFATc2, which are Ca2+/calmodulin‐sensitive transcription factors, resulting in increased cell proliferation. Knockdown of STIM2 in IPAH PASMCs decreased basal [Ca2+]cyt, phosphorylated‐Akt and mTOR levels, and reduced the activation of CREB, STAT3 and NFATc2, leading to decreased cell proliferation. The generalized upregulation of STIM2 in human PAH may overload intracellular Ca2+ and be a therapeutic target and biomarker.Support or Funding InformationThis work was supported in part by the grants from the National Heart, Lung and Blood Institute of the National Institutes of Health (HL115014, HL066012 and HL125208).