TY - JOUR
T1 - MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension
T2 - Results of a network bioinformatics approach
AU - Parikh, Victoria N.
AU - Jin, Richard C.
AU - Rabello, Sabrina
AU - Gulbahce, Natali
AU - White, Kevin
AU - Hale, Andrew
AU - Cottrill, Katherine A.
AU - Shaik, Rahamthulla S.
AU - Waxman, Aaron B.
AU - Zhang, Ying Yi
AU - Maron, Bradley A.
AU - Hartner, Jochen C.
AU - Fujiwara, Yuko
AU - Orkin, Stuart H.
AU - Haley, Kathleen J.
AU - Barabási, Albert László
AU - Loscalzo, Joseph
AU - Chan, Stephen Y.
PY - 2012/3/27
Y1 - 2012/3/27
N2 - 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.
AB - 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.
KW - microRNA
KW - molecular biology
KW - network biology
KW - pulmonary heart disease
KW - vasculature
UR - http://www.scopus.com/inward/record.url?scp=84862777565&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.111.060269
DO - 10.1161/CIRCULATIONAHA.111.060269
M3 - Article
C2 - 22371328
AN - SCOPUS:84862777565
SN - 0009-7322
VL - 125
SP - 1520
EP - 1532
JO - Circulation
JF - Circulation
IS - 12
ER -