Project Details
Description
PROJECT SUMMARY
Pulmonary Arterial Hypertension (PAH) is a progressively debilitating and eventually lethal disease,
whereby only the symptoms are treated by current therapeutics. A defining characteristic of PAH is the
excessive cellular proliferation and remodeling of pulmonary arteries (PA) that results in increased
vascular resistance and stiffness, and eventually failure of the right ventricle and death. PAH has a
survival time of less than five-years post diagnosis, and current treatment strategies are self-limiting in
that they do not sufficiently prolong survival time or reverse the pathologic vascular remodeling. In the
previous funding period we established an important role for Galectin-3 (Gal-3) in mediating aberrant
pulmonary vascular remodeling, and demonstrated that Gal-3 knockout rats are protected from PAH and
further showed the ability of pharmacological inhibitors of Gal-3 to prevent and reverse established PAH.
Gal-3 expression was also found in pulmonary arterial smooth muscle cells (PASMC), where it promoted
proliferation, migration and resistance to apoptosis.
In preliminary data for this competitive renewal, we find that HIF2α robustly upregulates Gal-3 expression.
Along these lines, we have uncovered a novel HIF2α binding site on the LGALS3 promoter, and using a
capsid modified AAV2 that specifically targets lung endothelial cells (EC), we also show that increased
expression of HIF2α in PAEC in vivo increases Gal-3 and promotes pulmonary hypertension in mice. In
co-culture experiments we show that upregulation of HIF2α in the endothelium can promote increased
Gal-3 expression in the underlying PASMC and enhance proliferation. We also identified DNA
methylation as a major regulator of Gal-3 expression as the DNA methyltransferase, DNMT3A was
downregulated in PAH. Further, silencing DNMT3A increased Gal-3 expression, and a dCas9-DNMT3A
fusion directed to the Gal-3 promoter, decreased Gal-3 expression. In vitro, the combination of hypoxia
and loss of DNA methylation synergize to drive high level Gal-3 expression, and NEAT1 is a recently
described hypoxia regulated lncRNA that regulates smooth muscle cell phenotype and proliferation.
Towards this end, we found that NEAT1 expression is increased in human PAH lung as well as in PA
from MCT rats and is regulated by Gal-3 in PASMC. Our long term objectives are to 1. Determine the cell
specific role of Gal-3 in mediating vascular remodeling and PAH, 2. Investigate the role of DNA
methylation and DNMT3A in regulating Gal-3 expression and synergy with HIF2, and 3. Determine
whether Gal-3 regulation of NEAT1 in PASMC contributes to PAH.
Status | Finished |
---|---|
Effective start/end date | 2/1/16 → 1/31/25 |
Funding
- National Heart, Lung, and Blood Institute: $538,001.00
- National Heart, Lung, and Blood Institute: $538,001.00
- National Heart, Lung, and Blood Institute: $630,630.00
- National Heart, Lung, and Blood Institute: $538,001.00
- National Heart, Lung, and Blood Institute: $700,700.00
- National Heart, Lung, and Blood Institute: $700,700.00
- National Heart, Lung, and Blood Institute: $538,001.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.