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

作者：Chen, Jidong; Cui, Xiaolei; Qian, Zhengjiang; Li, Yanjiao; Kang, Kang; Qu, Junle; Li, Li^*; Gou, Deming^*

来源：BMC Genomics, 2016, 17(1): 781.

DOI：10.1186/s12864-016-3122-3

• Platelet-derived growth factor-BB (PDGF-BB)
• Pulmonary arterial hypertension (PAH)
• RNA sequencing
• iTRAQ
• BMPR2
• miR-376b

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.

• 出版日期2016-10-6
• 单位深圳大学