RNA sequencing analysis of monocrotaline-induced PAH reveals dysregulated chemokine and neuroactive ligand receptor pathways

Abstract

Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevated pulmonary artery pressure, inflammatory cell infiltration and pulmonary vascular remodeling. However, little is known about the pathogenic mechanisms underlying the disease onset and progression. RNA sequencing (RNA-seq) was used to identify the transcriptional profiling in control and rats injected with monocrotaline (MCT) for 1, 2, 3 and 4 weeks. A total of 23200 transcripts and 280, 1342, 908 and 3155 differentially expressed genes (DEGs) were identified at the end of week 1, 2, 3 and 4, of which Svop was the common top 10 DEGs over the course of PAH progression. Functional enrichment analysis of DEGs showed inflammatory/immune response occurred in the early stage of PAH development. KEGG pathway enrichment analysis of DEGs showed that cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction were in the initiation and progression of PAH. Further analysis revealed impaired expression of cholinergic receptors, adrenergic receptors including alpha1, beta1 and beta2 receptor, and dysregulated expression of γ-aminobutyric acid receptors. In summary, the dysregulated inflammation/immunity and neuroactive ligand receptor signaling pathways may be involved in the onset and progression of PAH.

Transcriptomic analysis identifies Toll‐like and Nod‐like pathways and necroptosis in pulmonary arterial hypertension

“…Our previous study has showed the elevated markers of macrophage infiltration and inflammatory mediators, such as TNFα and IL‐6, with concomitantly increased pulmonary arterial remodelling parameters WT% and WA% in the progression of MCT‐induced PAH 7 . RNA‐seq analysis of rat lungs isolated from control and MCT‐treated rats identified a total of 23 200 transcripts, of which 280, 1342, 908 and 3155 were differentially expressed at the end of weeks 1, 2, 3 and 4, respectively 10 . Further hierarchical clustering analysis of the differentially expressed genes (DEGs) revealed 10 clusters of expression pattern.…”

“…9 We have performed RNA-seq analysis of rat lungs isolated from control and monocrotaline (MCT)-treated rats that had been treated with MCT for a variety of weeks, and this study showed that inflammatory and immune response was occurred at the early time-point of PAH development and dysregulated inflammation/immunity were involved in the onset and progression of PAH. 10 The changes of inflammation and immunity and pulmonary vascular remodelling that occur during the PAH progression largely result from the changes in the transcriptome. Therefore, in the current study, we use the RNA-seq data set and bioinformatics approach to carry out a further analysis of the transcriptome in MCT-induced PAH, aiming to have a deeper understanding of inflammatory and immune mechanisms in pulmonary vascular remodelling.…”

“…Recently, high‐throughput RNA sequencing (RNA‐seq) has emerged as a more powerful alternative to microarray 9 . We have performed RNA‐seq analysis of rat lungs isolated from control and monocrotaline (MCT)‐treated rats that had been treated with MCT for a variety of weeks, and this study showed that inflammatory and immune response was occurred at the early time‐point of PAH development and dysregulated inflammation/immunity were involved in the onset and progression of PAH 10 …”

Pyrrolizidine alkaloid-induced transcriptomic changes in rat lungs in a 28-day subacute feeding study

“…However, only a few studies evaluated the effects of PAs in gene expression in the lung or in human lung cells. Most of the studies focused on monocrotaline since this PA is often used to induce PAH in rats (Xiao et al 2020;Kishimoto et al 2015;Fu et al 2014). Therefore, the present study aimed to provide information which pathways are affected in rat lung after repeated-dose exposure to six structurally different PAs.…”

“…The phytotoxins can be found for example in Senecio jacobeae, which is resident in Western Europe, South Africa, Australia, New Zealand, and North America (Stegelmeier et al 1999). Furthermore, many other plants from families like Boraginaceae (all genera), Asteraceae (tribes Senecioneae and Eupatorieae) and Fabaceae contain PAs (Wiedenfeld et al 2008), which are produced as a defense mechanism against herbivores. They are synthesized in an estimated number of 6000 plant species and show a huge structural variety (EFSA 2011;Teuscher and Lindequist 2009).…”