title: Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy.
abstract: Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated αB-crystallin (CryAB(R120G)), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB(R120G) model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of α-tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB(R120G) cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB(R120G) TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease.
authors.affiliation: The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McLendon
authors.affiliation: Department of Medicine, Division of Cardiology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.affiliation: The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.affiliation: The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
authors.forename: Md Shenuarin
authors.initials: MS
authors.lastname: Bhuiyan
authors.affiliation: The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and.
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.affiliation: Department of Medicine, Division of Cardiology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.affiliation: The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and jeff.robbins@cchmc.org.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects / Q000502:physiology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000378:metabolism*; D000077337:Vorinostat; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; D038203:alpha-Crystallin B Chain; D000077337:Vorinostat; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; alphaB-crystallin; autophagy; heart; proteotoxicity