title: Dissecting histone deacetylase role in pulmonary arterial smooth muscle cell proliferation and migration.
abstract: Pulmonary Arterial Hypertension (PAH) is a rare and devasting condition characterized by elevated pulmonary vascular resistance and pulmonary artery pressure leading to right-heart failure and premature death. Pathologic alterations in proliferation, migration and survival of all cell types composing the vascular tissue play a key role in the occlusion of the vascular lumen. In the current study, we initially investigated the action of selective class I and class II HDAC inhibitors on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) after exposure to Platelet Derived Growth Factor (PDGF). Class I HDAC inhibitors were able to counteract the hyperproliferative response to PDGF, reducing both proliferation and migration in PASMCs, while class II were ineffective. Selective silencing with siRNAs targeted against different HDACs revealed a major role of class I, and within this class, of HDAC1 in mediating PDGF-induced Akt Phosphorylation and Cyclin D1 (CycD1) expression. These results from these combinatorial approaches were further confirmed by the ability of a specific HDAC1 inhibitor to antagonize the PDGF action. The finding that HDAC1 is a major conductor of PDGF-induced patterning in PAH-PASMCs prompts the development of novel selective inhibitors of this member of class I HDACs as a potential tool to control lung vascular homeostasis in PAH.
authors: National Institute of Biostructures and Biosystems (NIBB), University of Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Margherita
authors: M
authors: Galletti
authors: National Institute of Biostructures and Biosystems (NIBB), University of Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. Electronic address: silcant@gmail.com.
authors: Silvia
authors: S
authors: Cantoni
authors: National Institute of Biostructures and Biosystems (NIBB), University of Bologna, Bologna, Italy; Società Italiana Studi Medicina della Riproduzione (S.I.S.Me.R.), Reproductive Medicine Unit, Bologna, Italy.
authors: Filippo
authors: F
authors: Zambelli
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Sabrina
authors: S
authors: Valente
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Massimiliano
authors: M
authors: Palazzini
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Alessandra
authors: A
authors: Manes
authors: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Gianandrea
authors: G
authors: Pasquinelli
authors: Department of Drug Chemistry & Technologies, Sapienza University of Rome, Rome, Italy.
authors: Antonello
authors: A
authors: Mai
authors: National Institute of Biostructures and Biosystems (NIBB), University of Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
authors: Nazzareno
authors: N
authors: Galiè
authors: National Institute of Biostructures and Biosystems (NIBB), University of Bologna, Bologna, Italy; Stem Wave Institute for Tissue Healing (SWITH), Gruppo Villa Maria (GVM) and Ettore Sansavini Health Foundation - ONLUS, Lugo, Ravenna, Italy.
authors: Carlo
authors: C
authors: Ventura
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000737:chemistry*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C583610:MC1575; D010982:Platelet-Derived Growth Factor; D011758:Pyrroles; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases
keywords: Histone deacetylase; Migration; Proliferation; Pulmonary hypertension; Smooth muscle cells