Integration of Genome-Wide MicroRNA and mRNA Expression Profiles in Pulmonary Arterial Hypertension and Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis
Objective: To determine the role of microRNAs in the pathogenesis of pulmonary arterial hypertension (PAH).
Background: PAH is a life-threatening condition characterized by pulmonary arteriolar remodeling, progressive elevation of pulmonary artery pressure, and right heart failure. The genomic mechanisms of PAH remain ill defined. We have recently reported genome-wide lung tissue mRNA expression changes associated with PAH and pulmonary hypertension (PH) associated with idiopathic pulmonary fibrosis (IPF). We now report expression changes of microRNAs, which are small RNAs that play a key role in the post transcriptional regulation of mRNAs.
Methods: Using microarrays, we generated microRNA expression profiles in lung tissue from subjects with PAH (n = 18), PH associated with IPF (n = 5), and normal controls (n = 10); and integrated these microRNA expression data with our previously published mRNA expression data from the same subjects.
Results: Expression of 23 microRNAs was significantly increased in PAH relative to normal controls (q≤0.05). Of these, miR-33a, miR-101*, and miR-144 were also increased in PAH relative to PH associated with IPF. Integration of predicted gene targets of these 23 microRNAs with our previous mRNA dataset identified 910 genes as being downregulated by these microRNAs. The above mentioned microRNAs along with miR-21* and miR-410 were identified as key players in the pathogenesis of PAH based on their role in different biological networks and pathways. Expression changes in these microRNAs were confirmed by QPCR. All five microRNAs were integral to the cellular growth and proliferation network. They also downregulated several genes in the TGFβ pathway, including those previously implicated in PAH such as, BMPR2, BMPR1A, ACVR1, SMAD2/4. Other affected pathways included, protein ubiquitination, ERK/MAPK, β-adrenergic, nitric oxide and PDGF signaling.
Conclusions: We have identified microRNAs that may be critical in the development of PAH. This is the first study to integrate mRNA expression data with microRNA expression data on a genome-wide basis in PAH. It may be possible in the future to attenuate or even to reverse pathological changes in the expression of mRNAs in many biological pathways by targeting a few microRNAs.
Rajkumar, R; Shariff, AI; Choi, J-I; Huang, GT; Pandit, KV; Sembrat, JC; Ishizawar, DC; Richards, TJ; Benos, PV; Kaminski, N; Ahmad, F
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