Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Dec;70(23):4479-94.
doi: 10.1007/s00018-013-1382-5. Epub 2013 Jun 6.

MicroRNAs in pulmonary arterial remodeling

Jennifer S Grant  1 , Kevin White, Margaret R MacLean, Andrew H Baker
Affiliations
Review

MicroRNAs in pulmonary arterial remodeling

Jennifer S Grant et al. Cell Mol Life Sci. 2013 Dec.

Abstract

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Pathogenesis of pulmonary arterial hypertension. Stress to the small pulmonary arteries results in endothelial dysregulation and proliferation in the intima, smooth muscle cell proliferation, and resistance to apoptosis within the medial layer, along with adventitial fibroblast activation. This culminates in vasoconstriction and remodeling of the pulmonary vessels, which can result in plexiform lesions in human PAH
Fig. 2
Fig. 2
MiRNA biogenesis. Transcription by RNA polymerase II gives rise to the pri-miRNA, which can produce multiple mature miRNAs. Processing by RNase III enzyme Drosha along with cofactor DGCR8 produces the stem-loop pre-miRNA which is exported out of the nucleus by Exportin-5. In the cytoplasm, cleavage by Dicer results in an miRNA duplex, ~22 nucleotides long. The mature miRNA is incorporated into the RNA-induced silencing complex (RISC) and targets the 3′-UTR of mRNA. Gene silencing is achieved by either mRNA degradation or translational repression
Fig. 3
Fig. 3
MiRNA regulatory pathways. Summary schematic illustrating the complex pathways controlled by miRNAs. Dysregulation of endothelial cells (EC) and smooth muscle cells (SMC) can occur in response to stress or injury to the vessel leading to vasoconstriction and pulmonary arterial remodeling
See this image and copyright information in PMC

References

    1. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):40S–47S. - PubMed
    1. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–S54. - PubMed
    1. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26(1):81–84. - PubMed
    1. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006;27(2):121–132. - PubMed
    1. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA, Loyd JE. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. 2001;345(5):319–324. - PubMed

Publication types

MeSH terms