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Comprehensive transcriptome analysis of lung tissues in the sugen/hypoxia rats with/without treatment of chrysin or trimetazidine

ABSTRACT: Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by high blood pressure in the pulmonary artery. Chrysin (5,7-dihydroxyflavone) is a phytochemical, which is a flavonoid widely present in plant sources. It is known that right ventricular dysfunction is the worst mortality predictor in patient with PAH. Recent studies have shown that chrysin improves hemodynamic parameters including right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in a rat model of chronic hypoxia-induced pulmonary hypertension. On the other hand, trimetazidine (TMZ) is an anti-ischemic agent widely used in the treatment of coronary artery disease. It has been reported that trimetazidine therapy for 3 months on top of standard PAH regime significantly improve right ventricular ejection fraction and functional capacity in patient with PAH. However, the effects of chrysin or trimetazidine on gene expression in lung of patient with PAH. Here, we performed that a comprehensive analysis of gene expression changes in lung tissues of sugen-received rats under hypoxic conditions, which is a model of PAH with chrysin or trimetazidine treatment using RNA sequencing (RNA-seq).

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE186996 | GEO | 2024/05/16

REPOSITORIES: GEO

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Project description:Pulmonary arterial hypertension (PAH) is a progressive disorder leading to occlusive vascular remodeling. Current PAH therapies improve quality of life but do not reverse structural abnormalities in the pulmonary vasculature. Here, we used a high-throughput drug screen combined with in silico analyses of existing transcriptomic datasets to identify a promising lead compound to reverse PAH. Induced pluripotent stem cell-derived endothelial cells (iPSC-EC) generated from six patients with PAH were exposed to 4,500 compounds and assayed for improved cell survival after serum withdrawal using a chemiluminescent caspase assay. Subsequent validation of caspase activity and improved angiogenesis combined with in silico analyses using the Gene Expression Omnibus (GEO ) and Library of Integrated Network-Based Cellular Signatures (LINCS) databases revealed that the lead compound AG1296 was positively associated with an anti-PAH gene signature. AG1296 increased abundance of bone morphogenetic protein receptors (BMPR2 and Ia), downstream signaling and gene expression, and suppressed PAH smooth muscle cell proliferation. AG1296 induced regression of pulmonary arterial (PA) neointimal lesions in lung organ culture and PA occlusive changes in the Sugen/hypoxia rat model and reduced right ventricular systolic pressure. Moreover, AG1296 improved vascular function and BMPR2 signaling and showed better correlation with the anti-PAH gene signature than other tyrosine kinase inhibitors (TKIs) such as imatinib. Specifically, AG1296 upregulated the transcription factors and small mothers against decapentaplegic (SMAD)1/5 co-activators, cAMP-response element binding protein (CREB)3 and CREB5: CREB3 induced inhibitor of DNA binding 1 (ID1) and downstream genes that improved vascular function. Thus, drug discovery for PAH can be accelerated by combining a phenotypic screen using patient-specific iPSC-derived vascular cells with in silico analyses of publicly available datasets.

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Comprehensive transcriptome analysis of lung tissues in the sugen/hypoxia rats with/without treatment of chrysin or trimetazidine

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