Multi-omics analysis reveals regulators of the response to PDGF-BB treatment in pulmonary artery smooth muscle cells

• Published in: BMC genomics Vol. 17; no. 1; p. 781
• Main Authors: Chen, Jidong, Cui, Xiaolei, Qian, Zhengjiang, Li, Yanjiao, Kang, Kang, Qu, Junle, Li, Li, Gou, Deming
• Format: Journal Article
• Language: English
• Published: London BioMed Central 06.10.2016; BioMed Central Ltd
• Subjects: Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Cluster Analysis; Comparative and evolutionary genomics; Complications and side effects; Gene Expression Profiling - methods; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Humans; Influence; Life Sciences; Microarrays; Microbial Genetics and Genomics; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Plant Genetics and Genomics; Platelet-derived growth factor; Proteomics; Proteomics - methods; Proto-Oncogene Proteins c-sis - pharmacology; Pulmonary Artery - metabolism; Pulmonary hypertension; Reproducibility of Results; Research Article; RNA Interference; Smooth muscle; Transcriptome; China; RNA sequencing; Pulmonary arterial hypertension (PAH); iTRAQ; miR-376b; BMPR2; Platelet-derived growth factor-BB (PDGF-BB)
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-016-3122-3

Background Pulmonary arterial hypertension (PAH) is a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell proliferation. The platelet-derived growth factor BB (PDGF-BB) is well known as a potent mitogen for smooth muscle cell proliferation. To better understand how this growth factor regulates pulmonary arterial smooth muscle cells (PASMCs) proliferation, we sought to characterize the response to PDGF-BB stimulation at system-wide levels, including the transcriptome and proteome. Results In this study, we identified 1611 mRNAs (transcriptome), 207 proteins (proteome) differentially expressed in response to PDGF-BB stimulation in PASMCs based on RNA-sequencing and isobaric tags for relative and absolute quantification (iTRAQ) assay. Transcription factor (TF)-target network analysis revealed that PDGF-BB regulated gene expression potentially via TFs including HIF1A, JUN, EST1, ETS1, SMAD1, FOS, SP1, STAT1, LEF1 and CEBPB. Among them, SMAD1-involved BMPR2/SMADs axis plays a significant role in PAH development. Interestingly, we observed that the expression of BMPR2 was decreased in both mRNA and protein level in response to PDGF-BB. Further study revealed that BMPR2 is the direct target of miR-376b that is up-regulated upon PDGF-BB treatment. Finally, EdU incorporation assay showed that miR-376b promoted proliferation of PASMCs. Conclusion This integrated analysis of PDGF-BB-regulated transcriptome and proteome was performed for the first time in normal PASMCs, which revealed a crosstalk between PDGF signaling and BMPR2/SMADs axis. Further study demonstrated that PDGF-BB-induced miR-376b upregulation mediated the downregulation of BMPR2, which led to expression change of its downstream targets and promoted proliferation of PASMCs.