Differentially Expressed Genes and Pathways between Reversible and Irreversible Pulmonary Arterial Hypertension Associated with Congenital Heart Disease Investigated by Bioinformatics Analysis in Rat Model

Abstract

Abstract Background Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is one of the common types of PAH. Although the treatments of PAH–CHD are greatly advanced, it is still characterized by a poor prognosis, especially in its irreversible stage. The molecular mechanism underpinning the transition from the reversible stage to the irreversible stage is not well established. Methods and results GSE149899 was downloaded from Gene Expression Omnibus database, which is a dataset harvested from rat PH model induced by monocrotaline together with aortocaval shunt ((control (n = 5), reversible (n = 12), irreversible (n = 6)). R software was used to determine 252, 445, and 880 differentially expressed genes (DEGs) between the control group and the reversible PAH-CHD, the control group and the irreversible PAH-CHD, the reversible and irreversible PAH-CHD, respectively. Furthermore, we analyzed the biological functions of these DEGs. We concluded that common DEGs between reversible and irreversible PAH-CHD mainly enriched in the cell cycle, the p53 signaling pathway. The unique DEGs of reversible PAH-CHD involved in cell cycle, base excision repair. DEGs exclusively found in irreversible PAH-CHD were associated with complement and coagulation cascades, ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway. Additionally, The P53 signaling pathway, ferroptosis, PI3K-Akt signaling pathway, IL-17 signaling pathway, cell cycle, complement and coagulation cascades were up-regulated both in reversible and irreversible groups, but up-regulation of the PI3K-Akt signaling pathway, cell cycle were more pronounced in the reversible group, whereas ferroptosis and complement and coagulation cascades was more pronounced in the irreversible group. The TNF signaling pathway, cellular senescence, and the AGE-RAGE signaling pathway were exclusively up-regulated in the reversible group, while the renin-angiotensin system was up-regulated and the AMPK signaling pathway was down-regulated exclusively in the irreversible groups. Conclusions The distinguishing pathways and hub genes between reversible and irreversible PAH-CHD may be attributable to the loss of reversibility of PAH-CHD in the end stages, and may cast new light on future research.