Divergent Changes of p53 in Pulmonary Arterial Endothelial and Smooth Muscle Cells Involved in the Development of Pulmonary Hypertension.

The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, andsenescence. The non-canonical function or the pathogenic role of p53 has more recently been implicatedin pulmonary vascular disease.We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates TRPC channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+ ]cyt ). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (HPH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associatedwith an increased HIF-1α. Furthermore, p53 is downregulatedin PASMCs isolated from patients with idiopathic pulmonary arterial hypertension (IPAH) compared to PASMCs from normalsubjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum (SR), while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross-talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an importantrole in the development of pulmonary hypertension via, at least in part, induction of PAECs apoptosis and PASMCs proliferation.