title: Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK.
abstract: Smooth muscle in the pulmonary artery of PAH subjects, both idiopathic and hereditary, is characterized by hyperplasia. Smooth muscle cells (HPASMC) isolated from subjects with or without PAH retain their in vivo phenotype as illustrated by their expression of alpha-smooth muscle actin and expression of H-caldesmon. Both non PAH and PAH HPASMC display a lengthy, approximately 94h, cell cycle. The HPASMC from both idiopathic and hereditary PAH display an abnormal proliferation characterized by continued growth under non-proliferative, non-growth stimulated conditions. This effector independent proliferation is JNK and p38 MAP kinase dependent. Blocking the activation of either abrogates the HPASMC growth. HPASMC from non PAH donors under quiescent conditions display negligible proliferation but divide upon exposure to growth factors such as PDGF-BB or FGF2 but not EGF. This growth does not involve the MAP kinases. Instead it routes via the tyrosine kinase receptor through mTOR and then 6SK. In the PAH cells PDGF-BB and FGF2 augment the dysregulated cell proliferation, also through mTOR/6SK. Additionally, blocking the activation of mTOR also modulates the MAP kinase promoted dysregulated growth. These results highlight key alterations in the growth of HPASMC from subjects with PAH which contribute to the etiology of the disease and can clearly be targeted at various regulatory points for future therapies.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Polgar
mesh_terms: D000077214:Becaplermin; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4