Abstract 19117: Epigenetic Regulation of Galectin-3 in Pulmonary Arterial Hypertension
Introduction: Pulmonary Arterial Hypertension (PAH) is a progressively debilitating disease that is resistant to current therapeutics. Defining characteristics of PAH include excessive cellular proliferation and remodeling of pulmonary arteries (PA) that increase vascular resistance and eventually promote right ventricle failure and death.
Hypothesis: Microarray analysis of isolated PA from models of PAH revealed increased Galectin-3 (Gal-3) that was confirmed by qRT-PCR and Western blot. Gal-3 is a β-galactoside binding lectin implicated in signaling pathways regulating cell proliferation, inflammation and fibrosis and has been identified as a biomarker of PAH in humans. However, the therapeutic utility of targeting Gal-3 in PAH and the mechanism underlying its overexpression are not yet known.
Results: We found that Gal-3 is upregulated in PA from multiple rat models of PAH including MCT, MCT + pneumonectomy, and SUGEN/hypoxia as well as human PAH and correlated with disease severity. Surprisingly, the bulk of Gal-3 expression was observed in the media of PA in both models and humans. To establish functional relevance, we employed selective inhibitors of Gal-3, which attenuated and reversed PA remodeling and functional indices of PAH in MCT-treated rats in vivo and reduced indices of proliferation and increased apoptosis in PA. Treatment of cultured human PASMC with various mitogens and vasoactive factors thought to be important in PAH, failed to increase Gal-3 expression. In contrast, isolated PASMC from rats with PAH exhibited an enduring capacity for increased proliferation and expressed higher levels of Gal-3 suggesting an epigenetic mechanism regulating Gal-3 expression. Treatment of PASMC with inhibitors of DNA methylation (Zebularine; 5-Aza-C) robustly increased Gal-3 expression. DNA methylation analysis of isolated PA, including pyrosequencing, revealed hypomethylation of DNA in animals with PAH. In contrast, inhibitors of HDACs reduced the expression of Gal-3 in both isolated PASMC and in PA from in vivo models of PAH together with improved pulmonary hemodynamics.
Conclusions: These results suggest an important role of epigenetic mechanisms in Gal-3 signaling and the enduring changes in vascular cell behavior observed in PAH.
Author Disclosures: D. Fulton: None. S. Barman: Other Research Support; Modest; We have received inhibitors of Galectin-3 from Galectin Therapeutics (Atlanta) at no cost.. F. Chen: None. X. Li: None. Y. Su: None. P. Traber: None. Z. Bordan: None. L. Meadows: None. S. Haigh: None. D. Stepp: None.
- © 2016 by American Heart Association, Inc.