miR-223 reverses experimental pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.

• Authors: Jolyane Meloche, Marie Le Guen, François Potus, Jérôme Vinck, Benoit Ranchoux, Ian Johnson, Fabrice Antigny, Eve Tremblay, Sandra Breuils-Bonnet, Frederic Perros, Steeve Provencher, Sébastien Bonnet
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 309 Issue 6 Pg. C363-72 (Sep 15 2015) ISSN: 1522-1563 [Electronic] United States
• PMID: 26084306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• MIRN223 microRNA, human
• MicroRNAs
• Monocrotaline
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Apoptosis (genetics)
• Cell Proliferation (physiology)
• Cells, Cultured
• DNA Damage (physiology)
• Down-Regulation (physiology)
• Female
• Humans
• Hypertension, Pulmonary (chemically induced, metabolism)
• Hypertrophy, Right Ventricular (genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Lung (drug effects, metabolism)
• Male
• MicroRNAs (metabolism)
• Middle Aged
• Monocrotaline (pharmacology)
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Pulmonary Artery (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)