title: Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte Interactions and Small Vessel Loss in Pulmonary Arterial Hypertension.
abstract: Reduced endothelial-pericyte interactions are linked to progressive small vessel loss in pulmonary arterial hypertension (PAH), but the molecular mechanisms underlying this disease remain poorly understood. To identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of patient-derived donor control and PAH lung pericytes followed by functional genomics analysis. Compared with donor control cells, PAH pericytes had significant enrichment of genes involved in various metabolic processes, the top hit being PDK4, a gene coding for an enzyme that suppresses mitochondrial activity in favor of glycolysis. Given reports that link reduced mitochondrial activity with increased PAH cell proliferation, we hypothesized that increased PDK4 is associated with PAH pericyte hyperproliferation and reduced endothelial-pericyte interactions. We found that PDK4 gene and protein expression was significantly elevated in PAH pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation. Importantly, reducing PDK4 levels restored mitochondrial metabolism, reduced cell proliferation, and improved endothelial-pericyte interactions. To our knowledge, this is the first study that documents significant differences in gene expression between human donor control and PAH lung pericytes and the link between mitochondrial dysfunction and aberrant endothelial-pericyte interactions in PAH. Comprehensive characterization of these candidate genes could provide novel therapeutic targets to improve endothelial-pericyte interactions and prevent small vessel loss in PAH.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California.
authors.forename: Ke
authors.initials: K
authors.lastname: Yuan
authors.affiliation: Stanford Cardiovascular Institute, Stanford University, Stanford, California; Division of Cardiology, Stanford University, Stanford, California.
authors.forename: Ning-Yi
authors.initials: NY
authors.lastname: Shao
authors.affiliation: Stanford Cardiovascular Institute, Stanford University, Stanford, California; Department of Pediatrics, Stanford University, Stanford, California.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hennigs
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California.
authors.forename: Marielle
authors.initials: M
authors.lastname: Discipulo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Orcholski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California.
authors.forename: Elya
authors.initials: E
authors.lastname: Shamskhou
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California.
authors.forename: Alice
authors.initials: A
authors.lastname: Richter
authors.affiliation: Department of Genetics, Stanford University, Stanford, California.
authors.forename: Xinqian
authors.initials: X
authors.lastname: Hu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University, Stanford, California; Division of Cardiology, Stanford University, Stanford, California.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California. Electronic address: vdejesus@stanford.edu.
authors.forename: Vinicio A
authors.initials: VA
authors.lastname: de Jesus Perez
mesh_terms: D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D059467:Transcriptome
chemical_list: C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases