Transcriptome analyses reveal common immune system dysregulation in PAH patients and -deficient rats.

Pulmonary arterial hypertension (PAH) is a severe disease caused by progressive distal pulmonary artery obstruction. One cause of PAH are loss-of-function mutations in the potassium channel subfamily K member 3 (KCNK3). KCNK3 encodes a two-pore domain potassium channel, which is crucial for pulmonary circulation homeostasis. However, our understanding of the pathophysiological mechanisms underlying KCNK3 dysfunction in PAH is still incomplete. Taking advantage of unique -deficient rats, we analyzed the transcriptomic changes in the lungs from homozygous -deficient rats and wild-type (WT) littermates and compared them to PAH patient transcriptomic data. Transcriptome analysis of lung tissue obtained from WT and -deficient rats identified 1915 down- or upregulated genes. In addition, despite limited similarities at the gene level, we found a strong common signature at the pathway level in PAH patients and -deficient rat lungs, especially for immune response. Using the dysregulated genes involved in the immune response, we identified Spleen Associated Tyrosine Kinase (SYK), a significantly downregulated gene in human PAH patients and -deficient rats, as a hub gene. Our data suggests that the altered immune system response observed in PAH patients may be partly explained by KCNK3 dysfunction through the alteration of SYK expression.