Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end-products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis.

METHODS AND RESULTS:

In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).

CONCLUSION:

We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.

• Authors: Jolyane Meloche, Antony Courchesne, Marjorie Barrier, Sophie Carter, Malik Bisserier, Roxane Paulin, Jean-François Lauzon-Joset, Sandra Breuils-Bonnet, Éve Tremblay, Sabrina Biardel, Christine Racine, Christian Courture, Pierre Bonnet, Susan M Majka, Yves Deshaies, Frédéric Picard, Steeve Provencher, Sébastien Bonnet
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 2 Issue 1 Pg. e005157 (Jan 16 2013) ISSN: 2047-9980 [Electronic] England
• PMID: 23525442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycation End Products, Advanced
• Indoles
• PPAR gamma
• Pyrroles
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• S100 Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Stat3 protein, rat
• Semaxinib
• Monocrotaline
• BMPR2 protein, human
• Bmpr2 protein, rat
• Bone Morphogenetic Protein Receptors, Type II

Topics

• Adult
• Aged
• Animals
• Apoptosis
• Arterial Pressure
• Bone Morphogenetic Protein Receptors, Type II (metabolism)
• Case-Control Studies
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Familial Primary Pulmonary Hypertension
• Female
• Glycation End Products, Advanced (metabolism)
• Humans
• Hypertension, Pulmonary (chemically induced, drug therapy, etiology, genetics, metabolism, pathology, physiopathology)
• Hypertrophy, Right Ventricular (etiology, metabolism, prevention & control)
• Hypoxia (complications)
• Indoles
• Male
• Middle Aged
• Monocrotaline
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology, physiopathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• PPAR gamma (metabolism)
• Pulmonary Artery (metabolism)
• Pyrroles
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (agonists, genetics, metabolism)
• S100 Proteins (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Transfection
• Up-Regulation