A Cross-Species and Sex-Specific Meta-Analysis of Transcriptomic Studies of Pulmonary Hypertension.

Abstract

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling and right ventricle (RV) dysfunction. Among the five PH groups, group 1 pulmonary arterial hypertension (PAH) is a particularly serious condition characterized by a poor prognosis. PAH can be in idiopathic (IPAH), associated (APAH), and heritable (HPAH) forms, and has a notable female predominance. A number of in vivo PH models in rodents together with in vitro cultured vascular cells such as pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients have been widely used to reproduce the pathological disease features. To systematically evaluate the in vivo and in vitro efficacy of the existing PH model systems, publicly available whole transcriptome data from both humans and rodents were collected and analyzed. Subgroups of Schistosoma-induced female PH in mice and male chronic hypoxia (CH)-PH model in rats correlated well with human HPAH and IPAH lungs, respectively. A SU5416-CH (SuHx) PH model is well connected to the decompensated RVs of human PAH. Sex dimorphisms have been observed in PAH derived PAECs and PASMCs, independent of gonadal hormones. We conducted, for the first time, a meta-cohort and cross-species comparative study and identified optimal in vivo and in vitro PH model systems that recapitulate certain aspects of the human PH, which could provide novel insights into new therapeutic avenues in PH.