title: Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity.
abstract: In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.
authors.affiliation: Department of Cell and Developmental Biology, 1156 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yin
authors.forename: Maozhen
authors.initials: M
authors.lastname: Zhang
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.forename: Martin
authors.initials: M
authors.lastname: Goettlicher
authors.forename: Patricia Ruiz
authors.initials: PR
authors.lastname: Noppinger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Victor A
authors.initials: VA
authors.lastname: Ferrari
authors.forename: Charles S
authors.initials: CS
authors.lastname: Abrams
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005333:Fetus; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007527:Isoenzymes; D012097:Repressor Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases