Abstract

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

Several studies have demonstrated that proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) play a pivotal role in the vascular remodelling characteristic of PAH. Levels of cytoplasmic calcium are an important determinant of PASMC proliferation and migration. The Plasma Membrane Calcium ATPase (PMCA) proteins extrude calcium from the cytosol to the extracellular medium.

Here, we have investigated whether inducers of PAH trigger any changes in the expression of PMCA genes in PASMCs. Treatment of PASMCs with the PAH inducers Platelet Derived Growth Factor (PDGF) or TNF-alpha induced a significant increase in the RNA levels of PMCA1. PMCA1 RNA levels are also elevated in lungs of rats with monocrotaline-induced PAH. In silico analysis of the PMCA1 gene promoter region has shown putative binding sites for the transcription factors NFAT and NFkB that could mediate the transcriptional upregulation triggered by PDGF and TNF-alpha respectively. However, we show here that upregulated PMCA1 gene expression is not mediated by binding of these transcription factors to the proximal promoter region. No changes were observed in the RNA levels of PMCA4, the other major PMCA isoform expressed in PASMCs.

Our results suggest an important role for PMCA1 in PASMC deregulation during PAH, although a full understanding of the role of PMCA1 on the onset and progression of PAH requires further investigation.