肺动脉高压（PAH）是一个进行性发展高死亡率的恶性疾病，表现为肺血管重塑和肺动脉高压。血管重塑表现为血管肌化、炎症和纤维化，目前缺乏有效治疗方案。本课题初步研究表明，半乳凝素-3（Gal-3）表达在3种不同的PAH模型肺动脉中明显升高，在动物和人的PAH动脉中膜平滑肌细胞Gal-3大量产生。在人肺动脉血管平滑肌细胞中，抑制Gal-3可以明显减少细胞增殖，纤维化和炎症反应。然而，Gal-3影响肺血管重塑的机制以及将Gal-3作为早期诊断和治疗靶点的价值还不清楚。本研究旨在1）证实Gal-3在PAH血管重塑中的作用，2）研究Gal-3在血管平滑肌细胞及其临近细胞中的作用及调控机制，3）探索Gal-3抑制剂在PAH治疗中的应用价值及意义。本项目的完成将有助于了解Gal-3在血管重塑中的作用、明确其在PAH中的转化潜力，发展Gal-3新型治疗药物将有助于逆转血管重塑，降低PAH发病率和病死率。

Progressive inward hypertrophic remodeling of pulmonary arteries is a defining characteristic of pulmonary arterial hypertension (PAH) and the therapeutic strategy of lowering pulmonary vascular resistance by reducing vascular tone is only temporarily effective and eventually failure of the right ventricle and death. Multiple signaling pathways which are involved in cellular proliferation, inflammation and fibrosis can cause pulmonary vascular remodeling in PAH, however the mechanisms are not yet well understood. Galectins are b-galactoside binding lectins that have been implicated as a nodal regulator of multiple signaling pathways involved in cellular proliferation, inflammation and fibrosis. We have found a member of Galectin proteins Galectin-3 (Gal-3) expression is increased in pulmonary vascular smooth muscle cells in remodeled PA. In cultured human pulmonary artery vascular smooth muscle cells (HPAVSMC), upregulation of Gal-3 expression promotes whereas inhibition of Gal-3 reduces proliferation, fibrosis and inflammation. However, the therapeutic utility of targeting Gal-3 in PAH and the mechanisms by which it influences pulmonary vascular remodeling are not yet known. This application will address the deficits in our knowledge by: 1) establishing a functional role of Gal-3 in the pathogenesis of PAH, 2) identifying the molecular regulatory mechanism of Gal-3 in pulmonary artery vascular smooth muscle cells in vascular remodeling, 3) exploring the significance of this pathway in PAH 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 improving the morbidity and mortality associated with PAH.