Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension.

Abstract

RATIONALE:

MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH).

OBJECTIVES:

To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.

METHODS:

We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells.

MEASUREMENTS AND MAIN RESULTS:

In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells.

CONCLUSIONS:

Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.

• Authors: Soni S Pullamsetti, Carmen Doebele, Ariane Fischer, Rajkumar Savai, Baktybek Kojonazarov, Bhola K Dahal, Hossein A Ghofrani, Norbert Weissmann, Friedrich Grimminger, Angelika Bonauer, Werner Seeger, Andreas M Zeiher, Stefanie Dimmeler, Ralph T Schermuly
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 185 Issue 4 Pg. 409-19 (Feb 15 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 22161164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antagomirs
• MIRN17 microRNA, human
• MIRN21 microRNA, mouse
• MicroRNAs
• Mirn17 microRNA, mouse
• Mirn92 microRNA, mouse
• Oligoribonucleotides
• antagomir-92a

Topics

• Airway Remodeling (drug effects)
• Animals
• Antagomirs
• Blotting, Western
• Cardiac Output (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (drug therapy, metabolism)
• Mice
• MicroRNAs (antagonists & inhibitors, metabolism, physiology)
• Oligoribonucleotides (pharmacology, therapeutic use)
• Pulmonary Artery (drug effects, physiology)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Resistance (drug effects)
• Ventricular Function, Right (drug effects)