Immune Cells in Pulmonary Arterial Hypertension

Ni, Silu; Ji, Tiantian; Dong, Jing; Chen, Fengqiang; Feng, Hao; Zhao, Huiying; Chen, Dekun; Ma, Wentao

doi:10.1016/j.hlc.2022.02.007

Cited by 10 publications

(4 citation statements)

References 136 publications

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“…Activated immune cells are rapidly proliferating and are thus dependent on serine to function 24 . Moreover, PAH patients exhibit immune system abnormalities [25][26][27] . We hypothesised that the protective effect of serine on PAH may be mediated via immunomodulation.…”

Section: There Is No Mr Evidence That the Effect Of Serine On Pah Is ...mentioning

confidence: 99%

A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension

Alhathli

Julian

Girach

et al. 2023

Preprint

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Pulmonary arterial hypertension (PAH) exhibits phenotypic heterogeneity and variable response to therapy. The metabolome has been implicated in the pathogenesis of PAH, but previous works have lacked power to implicate specific metabolites. Mendelian randomisation (MR) is a method for causal inference between exposures and outcomes. Using GWAS summary statistics, we implemented hypothesis-free MR methodology to test for causal relationships between serum concentration of 575 metabolites and PAH. Unbiased MR causally associated five metabolites with risk of PAH after stringent multiple testing correction; of the five candidates, serine and homostachydrine were validated in a different larger PAH GWAS, and associated with clinical severity of PAH via direct measurement in an independent clinical cohort of 449 PAH patients. We used conditional and orthogonal approaches to explore the biology underlying our lead metabolites. A rare variant analysis demonstrated that loss of function (LOF) mutations within ATF4, a transcription factor responsible for upregulation of serine synthesis under conditions of serine starvation, are associated with higher risk for PAH. Homostachydrine is a xenobiotic metabolite that is structurally related to L-proline betaine, which has been previously linked to modulation of inflammation and tissue remodelling in PAH. Our MVMR analysis suggests that the effect of L-proline betaine is actually mediated indirectly via homostachydrine. Our data presents a new method for study of the metabolome in the context of PAH, and suggests several candidates for further evaluation and translational research.

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Section: There Is No Mr Evidence That the Effect Of Serine On Pah Is ...mentioning

confidence: 99%

A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension

Alhathli

Julian

Girach

et al. 2023

Preprint

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“…Significantly increased infiltration of macrophages, mast cells, T lymphocytes, B lymphocytes, dendritic cells, and monocytes has been found in the pulmonary vasculature of patients with PAH, and have a vital effect on pulmonary perivascular inflammation and pathological processes of PAH (Savai et al, 2012 ; Zhu et al, 2021 ; Wang et al, 2022 ). Increased macrophages, mast cells, and B cells could accelerate inflammatory responses and pulmonary vascular remodeling in PAH (Ni et al, 2022 ). Accordingly, the expression levels of various cytokines and chemokines have been observed to be elevated in PAH patients and animal models.…”

Section: Inflammation In Pahmentioning

confidence: 99%

The Role of Gut and Airway Microbiota in Pulmonary Arterial Hypertension

et al. 2022

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Pulmonary arterial hypertension (PAH) is a severe clinical condition that is characterized pathologically by perivascular inflammation and pulmonary vascular remodeling that ultimately leads to right heart failure. However, current treatments focus on controlling vasoconstriction and have little effect on pulmonary vascular remodeling. Better therapies of PAH require a better understanding of its pathogenesis. With advances in sequencing technology, researchers have begun to focus on the role of the human microbiota in disease. Recent studies have shown that the gut and airway microbiota and their metabolites play an important role in the pathogenesis of PAH. In this review, we summarize the current literature on the relationship between the gut and airway microbiota and PAH. We further discuss the key crosstalk between the gut microbiota and the lung associated with PAH, and the potential link between the gut and airway microbiota in the pathogenesis of PAH. In addition, we discuss the potential of using the microbiota as a new target for PAH therapy.

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“…PAH is caused by hyperproliferation of pulmonary arterial smooth muscle cells, apoptosis, and metabolism 10 , resulting in an abnormally elevated PAP and pulmonary vascular resistance (PVR), which may lead to progressive right heart failure and ultimately contribute to patient mortality, making PVR a major cause of death in individuals with PAH 11 , 12 . HIV-1 infection is considered to be one of the major causes of pulmonary arterial hypertension, triggering dysregulation of inflammatory and immune responses as well as endothelial dysfunction 13 , which serves as one of the crucial pathogenic mechanisms of PAH 14 . However, the etiology and pathogenesis of PAH remain incompletely elucidated, particularly in cases associated with HIV-1.…”

Section: Introductionmentioning

confidence: 99%

“…considered to be one of the major causes of pulmonary arterial hypertension, triggering dysregulation of inflammatory and immune responses as well as endothelial dysfunction 13 , which serves as one of the crucial pathogenic mechanisms of PAH 14 . However, the etiology and pathogenesis of PAH remain incompletely elucidated, particularly in cases associated with HIV-1.…”

mentioning

confidence: 99%

Identification of the shared hub gene signatures and molecular mechanisms between HIV-1 and pulmonary arterial hypertension

Mai,

Yang,

Xie

et al. 2024

Sci Rep

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The close link between HIV-1 infection and the occurrence of pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms of their interrelation remain unclear. The microarray data of HIV-1 and PAH were downloaded from GEO database. We utilized WGCNA to identify shared genes between HIV-1 and PAH, followed by conducting GO and pathway enrichment analyses. Subsequently, differentially genes analysis was performed using external validation datasets to further filter hub genes. Immunoinfiltration analysis was performed using CIBERSORT. Finally, hub gene expression was validated using scRNA-seq data. We identified 109 shared genes through WGCNA, primarily enriched in type I interferon (IFN) pathways. By taking the intersection of WGCNA important module genes and DEGs, ISG15 and IFI27 were identified as pivotal hub genes. Immunoinfiltration analysis and scRNA-seq results indicated the significant role of monocytes in the shared molecular mechanisms of HIV-1 and PAH. In summary, our study illustrated the possible mechanism of PAH secondary to HIV-1 and showed that the heightened IFN response in HIV-1 might be a crucial susceptibility factor for PAH, with monocytes being pivotal cells involved in the type I IFN response pathway. This provides potential new insights for further investigating the molecular mechanisms connecting HIV-1 and PAH.

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Immune Cells in Pulmonary Arterial Hypertension

Cited by 10 publications

References 136 publications

A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension

A Mendelian randomization study with clinical follow-up links metabolites to risk and severity of pulmonary arterial hypertension

The Role of Gut and Airway Microbiota in Pulmonary Arterial Hypertension

Identification of the shared hub gene signatures and molecular mechanisms between HIV-1 and pulmonary arterial hypertension

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