title: Novel Targets of Drug Treatment for Pulmonary Hypertension.
abstract: Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, promoters of proliferation and apoptosis resistance in PASMCs and endothelial cells, such as aberrant signal pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs, have also been described. As a result of these discoveries, PH is currently divided into subgroups based on the underlying pathology, which allows focused and targeted treatment of the condition. The defining features of PH, which subsequently lead to vascular wall remodeling, are dysregulated proliferation of PASMCs, local inflammation, and apoptosis-resistant endothelial cells. Efforts to assess the relative contributions of these factors have generated several promising targets. This review discusses recent novel targets of therapies for PH that have been developed as a result of these advances, which are now in pre-clinical and clinical trials (e.g., imatinib [phase III]; nilotinib, AT-877ER, rituximab, tacrolimus, paroxetine, sertraline, fluoxetine, bardoxolone methyl [phase II]; and sorafenib, FK506, aviptadil, endothelial progenitor cells (EPCs) [phase I]). While substantial progress has been made in recent years in targeting key molecular pathways, PH still remains without a cure, and these novel therapies provide an important conceptual framework of categorizing patients on the basis of molecular phenotype(s) for effective treatment of the disease.
authors.affiliation: Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, E1226 BST 200 Lothrop Street, Pittsburgh, PA, 15213, USA, jih67@pitt.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Qinzi
authors.initials: Q
authors.lastname: Xu
authors.forename: Charles
authors.initials: C
authors.lastname: McTiernan
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lai
authors.forename: David
authors.initials: D
authors.lastname: Osei-Hwedieh
authors.forename: Mark
authors.initials: M
authors.lastname: Gladwin
mesh_terms: D002986:Clinical Trials as Topic; D066026:Endothelial Progenitor Cells / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D035683:MicroRNAs / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D035703:Therapies, Investigational / Q000145:classification / Q000379:methods; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors