Investigational pharmacotherapy and immunotherapy of pulmonary arterial hypertension: An update

Yang, Yicheng; Lin, Fang-Chi; Xiao, Zhiqiang; Sun, Bo; Wei, Zhiyao; Liu, Bingyang; Xue, Liyan; Xiong, Chang-ming

doi:10.1016/j.biopha.2020.110355

Cited by 14 publications

(14 citation statements)

References 131 publications

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“…Investigations of effective treatment strategies and the underlying methods are still needed. Genetic dysfunction is commonly recognized as the underlying pathogenesis of IPAH, and immune disorders also play an essential role in disease progression [2]. Recently, the exploration of gene dysfunction and the immune landscape in IPAH has received unprecedented attention due to their great potential for reconstructing therapeutic ideas, which may improve the unsatisfactory treatment situation of IPAH.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the use of targeted drugs in the clinic, PAH remains a life-limiting disease. High pressure in the pulmonary artery is attributed to vasoconstriction, pulmonary vascular remodeling and vascular inflammation, and current research focuses on exploring more novel pathogenic mechanisms to reverse PAH; however, this Genes 2021, 12, 125 2 of 16 research still far from clinical practice [2]. Several genetic targets and immune patterns of PAH have been revealed [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Although genetic dysfunction is commonly regarded as the basic pathogenesis of IPAH, several known targeted genes explain only 15-30% of IPAH cases. Moreover, although recent studies have demonstrated that both bone morphogenetic protein (BMP) 9 [2] and prostacyclin synthase [6] genetic variants may also be involved in the pathogenesis of IPAH, they still fail to fully explain the cause of IPAH in patients, indicating that the genetic basis of IPAH needs further investigation. In addition, immune and inflammatory cells play essential roles in the pathology of IPAH [2], and studies of the immune landscape may be valuable for developing novel approaches to treat IPAH.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Yang

et al. 2021

Genes

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Gene dysfunction and immune cell infiltration play an essential role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We aimed to investigate the immune landscape and novel differentially expressed genes (DEGs) of IPAH. In addition, potential druggable molecular targets for IPAH were also explored. In this study, the GSE117261 dataset was reanalyzed to explore the immune landscape and hub DEGs of IPAH. Lasso Cox regression analysis and receiver operating characteristic curve analysis were performed to detect the predictive value of IPAH. Additionally, the underlying drug targets for IPAH treatment were determined by drug–gene analysis. IPAH was significantly associated with the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway as well as energetic metabolism dysfunction. We identified 31 upregulated and 39 downregulated DEGs in IPAH patients. Six hub genes, namely, SAA1, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were related to IPAH pathogenesis regardless of sex differences. Prediction model analysis showed that the area under the curve values of the hub DEGs except CXCR2 were all above 0.9 for distinguishing IPAH patients. In addition, the relative proportions of 5 subtypes of immune cells, namely, CD8+ T cells, CD4+ memory resting T cells, γ delta T cells, M1 macrophages, and resting mast cells, were significantly upregulated in the IPAH samples, while 6 subtypes of immune cells, namely, CD4+ naive T cells, resting NK cells, monocytes, M0 macrophages, activated mast cells, and neutrophils, were downregulated. Additionally, a total of 17 intersecting drugs targeting 5 genes, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were generated as potential druggable molecular targets for IPAH. Our study revealed the underlying correlations between genes and immune cells in IPAH and demonstrated for the first time that SAA1, CCL5, CXCR1, CCR1, and ADORA3 may be novel genetic targets for IPAH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Yang

et al. 2021

Genes

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“…In an animal model, some effect on the restoration of BMPR-II signaling animal was shown by administration of berberine, puerarin and ataluren [161]. What is more, apelin expression was seen to decrease in PAH and the administration of apelin or BMPR-II ligands may improve it [162].…”

Section: Immunotherapeutic Approachmentioning

confidence: 99%

Role of the Immune System Elements in Pulmonary Arterial Hypertension

Tomaszewski

Bębnowska

Hrynkiewicz

et al. 2021

JCM

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Pulmonary arterial hypertension (PAH) is a relatively rare disease, but, today, its incidence tends to increase. The severe course of the disease and poor patient survival rate make PAH a major diagnostic and therapeutic challenge. For this reason, a thorough understanding of the pathogenesis of the disease is essential to facilitate the development of more effective therapeutic targets. Research shows that the development of PAH is characterized by a number of abnormalities within the immune system that greatly affect the progression of the disease. In this review, we present key data on the regulated function of immune cells, released cytokines and immunoregulatory molecules in the development of PAH, to help improve diagnosis and targeted immunotherapy.

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“…Risk stratification for PAH is used to guide patient management and therapeutic strategies. 1 , 2 A comprehensive assessment is required since no single variable provides sufficient diagnostic and prognostic information. However, these assessments require experienced medical personnel, and are expensive and time-consuming.…”

Section: Introductionmentioning

confidence: 99%

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension

Yang

Zeng

Gao

et al. 2022

European Heart Journal Open

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Aims We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats. Methods and results In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained the amelioration of PAH. Conclusion Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat.

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Investigational pharmacotherapy and immunotherapy of pulmonary arterial hypertension: An update

Cited by 14 publications

References 131 publications

Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Role of the Immune System Elements in Pulmonary Arterial Hypertension

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension

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