Abstract 10916: Blocking MicroRNA-17 by Intravenous Injection of Antagomirs Improves Pulmonary Hemodynamics and Right Heart Function in Experimental Pulmonary Hypertension
Pulmonary hypertension (PH) is a disorder of the lung vasculature caused by increased pulmonary vascular resistance due to vasoconstriction and vascular remodeling. MicroRNAs (miRs) have gained attention since they regulate gene expression at the posttranscriptional level. Recently, it was demonstrated that among others, the expression of miR-21 and members of the miR-17-92 cluster (consisting of miR-17, -18a, -19a/b, -20a and -92a) was significantly altered in rat models of PH. The aim of the present study was to determine the role of miR-17, -21 or -92a in the pathogenesis of PH and to evaluate whether inhibition of these miRs may provide a novel therapeutic approach for PH treatment. To analyze the effect of miR-17, -21 or -92a inhibition on PH in vivo, we used two different rodent models of PH (chronic hypoxia mouse model, monocrotalin (MCT) rat model) and inhibited the miRs by i.v. injection of specific antagomirs (8 or 5 mg/kg). Although antagomir-17 (A-17), -21 and -92 all significantly improved vascular morphometry compared to control antagomir (A-Co) and PBS treated hypoxic mice (all p<0.05, n=5), only A-17 also reduced hypoxia-induced right ventricular hypertrophy (A-Co: 145±4%, A-17: 129±3%) and ameliorated pulmonary hemodynamics (p<0.05). Moreover, A-17 reduced the hypoxia-induced increase of hematocrit (A-Co: 155±6%, A-17: 119±3% of normoxic mice). Likewise, in the rat model, A-17 treatment significantly decreased MCT induced right ventricular wall thickening (A-Co: 308±7%, A-17: 231±10% of controls) and improved cardiac output (A-Co: 67±6%, A-17: 100±5%) as well as pulmonary artery acceleration time (A-Co: 43±4%, A-17: 69±6%). Concerning the molecular effects, we detected an increase of the mRNAs of the miR-17 targets p21 (177±30% of PBS control) and BMP receptor II (203+57% of PBS control) in the lungs of the A-17 treated rats. Consistently, in human pulmonary vascular smooth muscle cells (SMC) overexpression of miR-17 resulted in a significant downregulation of p21 mRNA (68±5%) and enhanced proliferation. In summary, our data demonstrate that inhibition of miR-17 improves pulmonary hemodynamics and right heart function in experimental PH by interfering with the expression of the cell cycle inhibitor p21 and potentially other targets.
- © 2010 by American Heart Association, Inc.