Iron Metabolism and Idiopathic Pulmonary Arterial Hypertension: New Insights from Bioinformatic Analysis

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare vascular disease with a poor prognosis, and the mechanism of its development remains unclear. Further molecular pathology studies may contribute to a comprehensive understanding of IPAH and provide new insights into diagnostic markers and potential therapeutic targets. Iron deficiency has been reported in 43-63% of patients with IPAH and is associated with reduced exercise capacity and higher mortality, suggesting that dysregulated iron metabolism may play an unrecognized role in influencing the development of IPAH. In this study, we explored the regulatory mechanisms of iron metabolism in IPAH by bioinformatic analysis. The molecular function of iron metabolism-related genes (IMRGs) is mainly enriched in active transmembrane transporter activity, and they mainly affect the biological process of response to oxidative stress. Ferroptosis and fluid shear stress and atherosclerosis pathways may be the critical pathways regulating iron metabolism in IPAH. We further identified 7 key genes (BCL2, GCLM, MSMO1, SLC7A11, SRXN1, TSPAN5, and TXNRD1) and 5 of the key genes (BCL2, MSMO1, SLC7A11, TSPAN5, and TXNRD1) as target genes may be regulated by 6 dysregulated miRNAs (miR-483-5p, miR-27a-3p, miR-27b-3p, miR-26b-5p, miR-199a-5p, and miR-23b-3p) in IPAH. In addition, we predicted potential IPAH drugs—celastrol and cinnamaldehyde—that target iron metabolism based on our results. These results provide insights for further definition of the role of dysregulated iron metabolism in IPAH and contribute to a deeper understanding of the molecular mechanisms and potential therapeutic targets of IPAH.

Iron deficiency and cardiovascular disease

“…Levels of hepcidin have been shown to be higher in idiopathic PAH than in healthy controls, which might be explained by various factors including BMPR2 (bone morphogenetic protein receptor type 2) mutation/downstream pathway dysfunction and enhanced inflammatory response. 104,110 At the same time, the intracellular iron overload which parallels the circulating ID leads to mitochondrial dysfunction and increases oxidative stress, which in turn contributes to the progression of PH by inducing pulmonary vascular remodelling. 110,111 In the Jackson Heart Study enrolling 2800 individuals, ID was not associated with PH, and there was no association between ferritin or serum iron concentration and PH.…”

The Therapeutic Roles of Cinnamaldehyde against Cardiovascular Diseases

“…Recently, interest in trace elements has elevated since their abilities to induce a multitude of microcosmic events affecting cell fate, particularly ferroptosis, an iron-dependent mediated form of cell death [ 151 ]. Bioinformatic data predicted that CA probably alleviated intracellular iron shortage to inhibit pulmonary vascular remodeling and reduce pulmonary artery pressure, then postponing the deterioration of PAH [ 159 ]. As the contribution of ferroptosis regulation to the pharmacological benefits of CA is largely unknown, detailed basic researches are rewarding to be employed for determining whether CA diminishes vascular injury by improving the activation of ferroptosis.…”

Regulatory T Cell-Related Gene Indicators in Pulmonary Hypertension

“… Li et al (2020 ) conducted a comprehensive miRNA–mRNA network analysis and identified that AQP9 was one of the five hub genes possibly involved in the pathogenesis of idiopathic PAH. TXNRD1 was also decreased and identified as an iron metabolism-associated hub gene in lungs of idiopathic PAH ( Zou et al, 2021 ). S100A8 , a ligand of receptor for advanced glycation end products, was overexpressed in PAH patient-derived pulmonary artery smooth muscle cells compared to those from non-PAH control subjects in the absence of any external growth stimulus ( Nakamura et al, 2018 ).…”