Multi-omics Analysis Reveal PDGF-BB Regulate Proliferation Of Pulmonary Artery Smooth Muscle Through MiRNAs

Pulmonary Artery Hypertension(PAH)is a fatal disease,abnormal proliferation of cells caused by pulmonary vascular remodeling is an important pathological features.Platelet-derived growth factor BB(PDGF-BB)is an effective mitogen of smooth muscle cell proliferation.In order to fully elucidate the mechanism of PDGF-BB in governing the proliferation of pulmonary artery smooth muscle cells(PASMCs),this paper integrates multiple histological data,including transcription,proteome and mi RNA group,to explore the effect of PASMC on PDGF-BB.In our study,1611 m RNAs were differentially expressed in PDGF-BB-stimulated PASMCs RNA sequencing,isotope-labeled relative and absolute mass spectrometry(i TRAQ)and S-Poly(T)plus mi RNA detection(Transcriptome),207 proteins(proteome)and 13 mi RNAs(mi RNA groups).The expression of PDGF-BB was regulated by 10 transcription factors such as HIF1 A,JUN,EST1,ETS1,SMAD1,FOS,SP1,STAT1,LEF1 and CEBPB by analyzing the transcription factor and target gene network by analyzing the transcription factor and target gene network.Among them,SMAD1 in BMPR2/SMADs signal pathway regulation plays a major role in the development of PAH.In combination with mi RNAs,we found that mi R-376 B was directly targeted to BMPR2 in 13 mi RNAs differentiated by PASMC after PDGF-BB stimulation,and BMPR2 protein was regulated at post-transcriptional level to regulate BMPR2 / SMADs pathway and Its downstream target gene expression,and ultimately promote the excessive proliferation of PASMC.At the same time,we further analyzed the expression profiles of mi RNAs identified in mi RNAs in Rats,and found that mi R-339 is a cardiovascular-specific highly expressed mi RNA,which is expressed by a variety of cytokines including PDGF-BB and Growth factor induced down regulation,and down regulated in pulmonary arteries of PAH rat models.Functional studies have shown that mi R-339 inhibits PASMC proliferation.Interestingly,mi R-339 only inhibits FGF2-induced proliferation without affecting PDGF-BB-induced proliferation.Mechanism research has found that the important linker protein FRS2 in the FGF signaling pathway is a possibility target gene for mi R-339.FRS2 down regulation only inhibited FGF2-induced proliferation of PASMC,consistent with the results of mi R-339.In conclusion,PDGF-BB can inhibit the proliferation of BMPR2/SMADs pathway and promote the proliferation of RPASMC by regulating two mi RNAs,are respectively mi R-376 b and mi R-339.In this study,which provides a new mechanism for the interpretation of PDGF-BB-induced PAH and provides a novel drug target for PAH therapy.