title: Heat shock protein upregulation protects against pacing-induced myolysis in HL-1 atrial myocytes and in human atrial fibrillation.
abstract: Atrial fibrillation (AF) causes myocyte stress by inducing structural changes, predominantly myolysis, which is related to the progression of AF. As heat shock proteins (Hsp) protect against cellular stress, their efficacy in preventing myolysis was investigated in a tachy-paced cell model for AF and in patients with AF. HL-1 atrial myocytes were subjected to tachy-pacing, which induced myolysis. Hsp overexpression was accomplished by a mild heat shock or by the drug geranylgeranylacetone (GGA). Hsp-gene-transfection studies were carried out to investigate roles of individual Hsp. In left and/or right atrial appendages from patients with paroxysmal (n=14), persistent (n=17) AF and controls (n=13) in sinus rhythm (SR), Hsp levels (Westerns) and localization (confocal microscopy) were determined. Heat shock and GGA administered prior to tachy-pacing resulted in almost complete protection against tachy-pacing-induced myolysis. Overexpression of Hsp27, but not of Hsp70, also provided complete protection against pacing-induced myolysis. In patients with paroxysmal AF, Hsp27 expression was significantly increased compared to SR and persistent AF. No changes in Hsp40, Hsc70, Hsp70 and Hsp90 expression levels were observed. Hsp27 levels correlated inversely with the duration of paroxysmal and persistent AF and the extent of myolysis. Furthermore, Hsp27 was localized on myofibrils in tachy-paced HL-1 myocytes and in human cardiomyocytes. These data demonstrate that upregulation of Hsp, especially Hsp27, protects tachy-paced atrial myocytes from myolysis. Therefore, the observed elevated Hsp27 expression in patients with paroxysmal AF might serve to protect myocytes from myolysis and limit the progression to persistent AF. Pharmacological induction of Hsp, with drugs such as GGA, may represent a novel therapeutic approach in AF.
authors.affiliation: Department of Radiation and Stress Cell Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. B.J.J.M.Brundel@med.umcg.nl
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Lei
authors.initials: L
authors.lastname: Ke
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: van Gelder
authors.forename: Harry J G M
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
mesh_terms: D000368:Aged; D000818:Animals; D020517:Atrial Appendage / Q000473:pathology; D001281:Atrial Fibrillation; D004224:Diterpenes / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006331:Heart Diseases / Q000209:etiology / Q000517:prevention & control*; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D008875:Middle Aged; D018832:Molecular Chaperones; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D004224:Diterpenes; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C031049:geranylgeranylacetone