Comprehensive identification of signaling pathways for idiopathic pulmonary arterial hypertension

2020 ◽  
Vol 318 (5) ◽  
pp. C913-C930
Author(s):  
Bingxun Liu ◽  
Liping Zhu ◽  
Ping Yuan ◽  
Glenn Marsboom ◽  
Zhigang Hong ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Intracellular Calcium ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cell Function ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Channel Blockers ◽  
Gpcr Signaling ◽  
Pulmonary Arterial

Whole exome sequencing (WES) was used in the research of familial pulmonary arterial hypertension (FPAH). CAV1 and KCNK3 were found as two novel candidate genes of FPAH. However, few pathogenic genes were identified in idiopathic pulmonary arterial hypertension (IPAH). We conducted WES in 20 unrelated IPAH patients who did not carry the known PAH-pathogenic variants among BMPR2, CAV1, KCNK3, SMAD9, ALK1, and ENG. We found a total of 4,950 variants in 3,534 genes, including 4,444 single-nucleotide polymorphisms and 506 insertions/deletions (InDels). Through the comprehensive and multilevel analysis, we disclosed several novel signaling cascades significantly connected to IPAH, including variants related to cadherin signaling pathway, dilated cardiomyopathy, glucose metabolism, immune response, mucin-type O-glycosylation, phospholipase C (PLC)-activating G protein-coupled receptor (GPCR) signaling pathway, vascular contraction and generation, and voltage-dependent Ca2+ channels. We also conducted validation studies in five mutant genes related to PLC-activating GPCR signaling pathway potentially involved in intracellular calcium regulation through Sanger sequencing for mutation accuracy, qRT-PCR for mRNA stability, immunofluorescence for subcellular localization, Western blotting for protein level, Fura-2 imaging for intracellular calcium, and proliferation analysis for cell function. The validation experiments showed that those variants in CCR5 and C3AR1 significantly increased the rise of intracellular calcium and the variant in CCR5 profoundly enhanced proliferative capacity of human pulmonary artery smooth muscle cells. Thus, our study suggests that multiple genetically affected signaling pathways take effect together to cause the formation of IPAH and the development of right heart failure and may further provide new therapy targets or putative clues for the present treatments such as limited therapeutic effectiveness of Ca2+ channel blockers.

scholarly journals Long-Term Survival in Idiopathic Pulmonary Arterial Hypertension Associated with Massive Pulmonary Artery Dilation

2011 ◽  
Vol 18 (3) ◽  
pp. e50-e51 ◽  
Author(s):  
Vanja Petrovic ◽  
Christopher J Ryerson ◽  
Robert D Levy
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Present Report ◽  
Pulmonary Arteries ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Channel Blockers ◽  
Term Survival ◽  
Long Term Survival ◽  
Pulmonary Arterial

The present report describes two patients with long-term survival after being diagnosed with idiopathic pulmonary arterial hypertension more than 20 years earlier. Both patients were treated with calcium channel blockers for several years and are currently maintained on bosentan, an oral endothelin receptor antagonist. Severe dilation of the main pulmonary arteries is present in both patients and may be related to long-term survival with idiopathic pulmonary arterial hypertension.

scholarly journals Vasodilator responsiveness in idiopathic pulmonary arterial hypertension: identifying a distinct phenotype with distinct physiology and distinct prognosis

2017 ◽  
Vol 7 (3) ◽  
pp. 588-597 ◽  
Author(s):  
David Langleben ◽  
Stylianos Orfanos
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Peripheral Blood ◽  
Integration Site ◽  
Leukemia Virus ◽  
Virus Genome ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
High Dose ◽  
Channel Blockers ◽  
Pulmonary Arterial

Within the cohort of patients suffering from idiopathic pulmonary arterial hypertension (IPAH) is a group that responds dramatically (VR-PAH) to an acute vasodilator challenge and that has excellent long-term hemodynamic improvement and prognosis on high dose calcium channel blockers compared with vasodilator non-responders (VN-PAH). For the purposes of diagnosing VR-PAH, there is to date no test to replace the acute vasodilator challenge. However, recent studies have identified markers that may aid in the identification of VR-PAH, including peripheral blood lymphocyte RNA expression levels of desmogelin-2 and Ras homolog gene family member Q, and plasma levels of provirus integration site for Moloney murine leukemia virus. Genome wide-array studies of peripheral blood DNA have demonstrated differences in disease specific genetic variants between VR-PAH and NR-PAH, with particular convergence on cytoskeletal function pathways and Wnt signaling pathways. These studies offer hope for future non-invasive identification of VR-PAH, and insights into pathogenesis that may lead to novel therapies. Examination of the degree of pulmonary microvascular perfusion in PAH has offered additional insights. During the acute vasodilator challenge, VR-PAH patients demonstrate true vasodilation with recruitment and increased perfusion of the capillary bed, while VN-PAH patients are unable to recruit vasculature. In the very few reports of lung histology, VR-PAH has more medial thickening in the precapillary arterioles, while VN-PAH has the classic histology of PAH, including intimal thickening. VR-PAH is a disorder with a phenotype distinct from VN-PAH and other types of PAH, and should be considered separately in the classification of PAH.

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

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 125
Author(s):  
Jing Xu ◽  
Yicheng Yang ◽  
Yuejin Yang ◽  
Changming Xiong
Keyword(s):  
T Cells ◽  
Pulmonary Arterial Hypertension ◽  
Mast Cells ◽  
Arterial Hypertension ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Molecular Targets ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Cox Regression Analysis ◽  
Pulmonary Arterial

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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