156 Inducers of pulmonary arterial hypertension upregulate the expression of plasma membrane calcium atpase 1 in pulmonary artery smooth muscle cells

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Abstract

Pulmonary arterial hypertension (PAH) is a chronic and life-threatening disease with high morbidity and mortality in adult and paediatric patients. PAH is characterised by a progressive narrowing and occlusion of small pulmonary arteries leading to increased pulmonary resistance, right ventricular hypertrophy, and, finally, right ventricular failure.

A large body of data has shown that proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key events in the vascular remodelling of pulmonary arteries that occurs during PAH. Levels of cytoplasmic calcium are an important determinant of PASMC proliferation and migration, and failure in maintaining appropriate levels of intracellular calcium are associated with PAH. The plasma membrane calcium ATPase (PMCA) proteins extrude calcium from the cytosol to the extracellular medium, and in doing so, play a critical role in the modulation of intracellular calcium levels. In this work, we have investigated whether inducers of PAH trigger any changes in the expression of PMCA proteins in PASMCs.

Analysis of RNA expression levels for PMCA genes has revealed that treatment of PASMCs with PDGF results in a significant increase in the level of the RNA encoding for the protein PMCA1. Interestingly, PMCA1 RNA levels were also elevated in lungs of rats with monocrotaline-induced PAH. No changes were observed in the RNA levels for PMCA4, the other major PMCA isoform expressed in PASMCs. Although previous studies on the regulation of PMCA1 gene expression have identified functional binding sites for the transcription factors NFAT in the PMCA1 promoter region, we show here that PDGF-mediated upregulation of PMCA1 transcriptional expression is independent of activation of the calcineurin/NFAT signalling pathway.

Our results suggest the involvement of PMCA1 in PASMC deregulation during PAH, although determination of the link between increased expression of PMCA1 and PAH requires further investigation.

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