MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: Results of a network bioinformatics approach

Victoria N. Parikh, Richard C. Jin, Sabrina Rabello, Natali Gulbahce, Kevin White, Andrew Hale, Katherine A. Cottrill, Rahamthulla S. Shaik, Aaron B. Waxman, Ying Yi Zhang, Bradley A. Maron, Jochen C. Hartner, Yuko Fujiwara, Stuart H. Orkin, Kathleen J. Haley, Albert László Barabási, Joseph Loscalzo, Stephen Y. Chan

Research output: Contribution to journalArticlepeer-review

Abstract (may include machine translation)

Background-Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli. Methods and Results-Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH. Conclusions-A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH.

Original languageEnglish
Pages (from-to)1520-1532
Number of pages13
JournalCirculation
Volume125
Issue number12
DOIs
StatePublished - 27 Mar 2012

Keywords

  • microRNA
  • molecular biology
  • network biology
  • pulmonary heart disease
  • vasculature

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