title: Sodium butyrate inhibits platelet-derived growth factor-induced proliferation and migration in pulmonary artery smooth muscle cells through Akt inhibition.
abstract: Sodium butyrate (BU) is a molecule that acts as a histone deacetylase inhibitor. As compared with its well-known antineoplastic/antiproliferative effects, little is known about BU action on vascular cell dynamics. An imbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is essential in the onset and progression of pulmonary arterial hypertension (PAH), a disease that is characterized by vascular lung derangement and that frequently has an unfavorable outcome. Here, we show that, in PASMCs of PAH rats, BU counteracted platelet-derived growth factor (PDGF)-induced Ki67 expression, and arrested the cell cycle, mainly at G0 /G1 . BU decreased proliferating cell nuclear antigen, c-Myc and cyclin D1 transcription and protein expression, while increasing p21 expression. BU reduced the transcription of PDGF receptor-β, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing, migration and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculin A. BU-treated cells showed a remarkable increase in acetylated Akt, indicating an inverse relationship between the levels of acetylated Akt and phospho-Akt. These findings may provide novel perspectives on the use of histone deacetylase inhibitors in PAH.
authors: Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Bologna, Italy.
authors: Silvia
authors: S
authors: Cantoni
authors: Margherita
authors: M
authors: Galletti
authors: Filippo
authors: F
authors: Zambelli
authors: Sabrina
authors: S
authors: Valente
authors: Francesca
authors: F
authors: Ponti
authors: Riccardo
authors: R
authors: Tassinari
authors: Gianandrea
authors: G
authors: Pasquinelli
authors: Nazzareno
authors: N
authors: Galiè
authors: Carlo
authors: C
authors: Ventura
mesh_terms: D000107:Acetylation; D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones; D065627:Familial Primary Pulmonary Hypertension; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D009025:Morpholines; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D002867:Chromones; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D010982:Platelet-Derived Growth Factor; D020148:Butyric Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016686:Monocrotaline; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt