title: Lamina-associated polypeptide 2alpha loss impairs heart function and stress response in mice.
abstract: BACKGROUND
  Lamina-associated polypeptide (LAP)2alpha is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2alpha lead to cardiac disorders in humans, we hypothesized that these factors may play important roles in heart development and adult tissue homeostasis.
  
  
  OBJECTIVE
  We asked whether the presence of LAP2alpha was required for normal cardiac function.
  
  
  RESULTS
  To study the molecular mechanisms of the disease, we analyzed heart structure and function in complete and conditional Lap2alpha(-/-) mice as well as Lap2alpha(-/-)/Mdx mutants. Unlike conditional deletion of LAP2alpha in late embryonic striated muscle, its complete knockout caused systolic dysfunction in young mice, accompanied by sporadic fibrosis in old animals, as well as deregulation of major cardiac transcription factors GATA4 and myocyte enhancer factor 2c. Activation of compensatory pathways, including downregulation of beta-adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic beta-adrenergic stimulation and stalled the progression of LAP2alpha-deficient hearts from hypertrophy toward cardiac failure. Dystrophin deficiency in an Mdx background resulted in a transient rescue of the Lap2alpha(-/-) phenotype.
  
  
  CONCLUSIONS
  Our data suggest a novel role of LAP2alpha in the maintenance of cardiac function under normal and stress conditions.
authors.affiliation: Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3, A-1030 Vienna, Austria.
authors.forename: Ivana
authors.initials: I
authors.lastname: Gotic
authors.forename: Michael
authors.initials: M
authors.lastname: Leschnik
authors.forename: Ursula
authors.initials: U
authors.lastname: Kolm
authors.forename: Mato
authors.initials: M
authors.lastname: Markovic
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Haubner
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Biadasiewicz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Metzler
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Roland
authors.initials: R
authors.lastname: Foisner
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004452:Echocardiography / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology
chemical_list: D000318:Adrenergic beta-Agonists; D004268:DNA-Binding Proteins; D016189:Dystrophin; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D008565:Membrane Proteins; D018006:Myogenic Regulatory Factors; C093413:lamina-associated polypeptide 2; D007545:Isoproterenol