Pulmonary Arterial Hypertension (PAH) is a progressively debilitating and eventually lethal disease that is resistant to 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 5 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. Aberrant vascular remodeling in PAH can originate from diverse mechanisms in the intima, media, and adventitia and involves increases in the masculinization of pulmonary blood vessels, fibrosis, and inflammation. A major obstacle in the development of effective therapeutics for polygenic diseases such as PAH has been an inability to effectively target the multiple pathogenic mechanisms. We have found that Gal-3 expression is increased in remodeled PA. Gal-3 is a ?-galactoside binding lectin that has been implicated as a nodal regulator of multiple signaling pathways involved in cellular proliferation, inflammation and fibrosis. However, the therapeutic utility of targeting Gal-3 in PAH and the mechanisms by which it influences pulmonary vascular remodeling are not yet known. In the current application, we present preliminary evidence that Gal-3 is robustly upregulated in PA from rats with monocrotaline (MCT), MCT + pneumonectomy (PN), and SUGEN/hypoxia (Su/H) induced PAH. In normotensive vessels, Gal-3 is present in both the media and adventitia. However, in animals and humans with PAH, we found remarkable induction of Gal-3 in the media where it overlaps with smooth muscle markers. In cultured human pulmonary arterial smooth muscle cells (HPASMC), increasing Gal-3 expression via adenovirus promotes proliferation whereas silencing Gal-3 reduces proliferation and collagen expression (fibrosis). Based on this novel preliminary data, our central hypothesis is that Gal-3 is a nodal regulator of proliferation and fibrosis in PA and contributes t pathologic vascular remodeling in PAH. This hypothesis will be tested using integrated molecular, genetic, cellular, imaging, and translational approaches in rodent models with the objective of defining mechanisms by which Gal-3 orchestrates changes in vascular remodeling, a hallmark of PAH. At their conclusion, the proposed studies will move the field forward by identifying the vascular role of Gal-3, and its translational potential in PAH. We anticipate the development of novel therapeutic agents targeting Gal-3 that will help reduce pulmonary arterial remodeling, and subsequently improve the morbidity and mortality associated with PAH.
Pulmonary arterial hypertension (PAH) is disease that is caused by structural changes in pulmonary arteries that promotes high pulmonary blood pressure and ultimately right heart failure and death. We have discovered a novel gene, Galectin-3 that regulates the remodeling of pulmonary arteries in models of PAH and show that inhibition of Galectin-3 reduces PAH. The major goal of our studies is to identify how Galectin-3 influences pulmonary artery remodeling and to establish Galectin-3 inhibitors as novel therapeutic agents to reduce PAH and improve the morbidity and mortality of a disease for which there are few effective therapeutic options.
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