title: Multi-omics analysis reveals regulators of the response to PDGF-BB treatment in pulmonary artery smooth muscle cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong, 518060, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Cui
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong, 518060, China.
authors.forename: Zhengjiang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong, 518060, China.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Physiology, Shenzhen University Health Science Center, Shenzhen, Guangdong, 518060, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Kang
authors.affiliation: Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong, 518060, China.
authors.forename: Junle
authors.initials: J
authors.lastname: Qu
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China. ylili@szu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences and Oceanography, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong, 518060, China. dmgou@szu.edu.cn.
authors.forename: Deming
authors.identifier: 0000-0002-3312-841X
authors.initials: D
authors.lastname: Gou
mesh_terms: D000818:Animals; D000077214:Becaplermin; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism*; D034622:RNA Interference; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin
keywords: BMPR2; Platelet-derived growth factor-BB (PDGF-BB); Pulmonary arterial hypertension (PAH); RNA sequencing; iTRAQ; miR-376b