title: The CRM1 nuclear export receptor controls pathological cardiac gene expression.
abstract: Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.
authors.affiliation: Myogen Inc., 7575 W. 103rd Ave., Westminister, CO 80021, USA. timothy.mckinsey@myogen.com
authors.forename: Brooke C
authors.initials: BC
authors.lastname: Harrison
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roberts
authors.forename: David B
authors.initials: DB
authors.lastname: Hood
authors.forename: Meghan
authors.initials: M
authors.lastname: Sweeney
authors.forename: Jody M
authors.initials: JM
authors.lastname: Gould
authors.forename: Erik W
authors.initials: EW
authors.lastname: Bush
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000263:Adenylate Kinase / Q000032:analysis / Q000378:metabolism; D018829:Adhesins, Bacterial / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D006655:Histone Deacetylases / Q000378:metabolism; D015151:Immunoblotting; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011233:Precipitin Tests; D012313:RNA / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation; D000097606:Exportin 1 Protein
chemical_list: D000263:Adenylate Kinase; D018829:Adhesins, Bacterial; D000911:Antibodies, Monoclonal; D009320:Atrial Natriuretic Factor; D005452:Fluoresceins; D005456:Fluorescent Dyes; D049452:Green Fluorescent Proteins; D006655:Histone Deacetylases; D028884:Karyopherins; D012313:RNA; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C085925:calcein AM