Patients with pulmonary arterial hypertension (PAH) can harbor mutations in several genes, most commonly in BMPR2. However, disease penetrance in patients with BMPR2 mutations is low. In addition, most patients do not carry known PAH gene mutations, suggesting that other factors determine susceptibility to PAH. To begin to identify additional genomic factors contributing to PAH pathogenesis, we exposed 32 mouse strains to chronic hypoxia. We found that the PL/J strain has extremely high right ventricular systolic pressure (RVSP; 86.58 mm Hg) but minimal lung remodeling. To identify potential genomic factors contributing to the high RVSP, RNAseq analysis of PL/J lung mRNAs and microRNAs (miRNAs) after hypoxia was performed, and it demonstrated that 4 of 43 upregulated miRNAs in the Dlk1-Dio3 imprinting region are predicted to target T cell marker mRNAs. These target mRNAs, as well as the numbers of T cells were downregulated. In addition, C5a and its receptor, C5AR1, were increased. Analysis of Rho-associated protein kinase (Rock) 2 mRNA expression, in the RhoA/Rock pathway, demonstrated a significant increase in PL/J. Inhibition of Rock2 ameliorated a portion of the elevated RVSP. In addition, we identified miR-150-5p as a potential regulator of Rock2 expression. In conclusion, we identified two possible pathways contributing to the hypoxia pulmonary hypertension phenotype of extreme RVSP elevation: aberrant T cell expression driven by hypoxia-induced miRNAs and increased expression of C5a and C5AR1. We suggest that the PL/J mouse will be a good model for seeking mechanism(s) of RVSP elevation in hypoxia-induced PAH.
Keywords: Dlk1-Dio3 imprinting region; immune cells; microRNA; proinflammatory cytokines.