title: AMP-activated protein kinase α1 regulates cardiac gap junction protein connexin 43 and electrical remodeling following pressure overload.
abstract: OBJECTIVE
  Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling.
  
  
  METHODS
  Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by "transverse aortic constriction" (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy.
  
  
  RESULTS
  TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1(-/-) mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1(-/-) mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK(WT) and constitutively active AMPK(γR70Q), but not by catalytically inactive AMPK(αK45R).
  
  
  CONCLUSIONS
  Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Alesutan
authors.forename: Jakob
authors.initials: J
authors.lastname: Voelkl
authors.forename: Florian
authors.initials: F
authors.lastname: Stöckigt
authors.forename: Sobuj
authors.initials: S
authors.lastname: Mia
authors.forename: Martina
authors.initials: M
authors.lastname: Feger
authors.forename: Uwe
authors.initials: U
authors.lastname: Primessnig
authors.forename: Mentor
authors.initials: M
authors.lastname: Sopjani
authors.forename: Carlos
authors.initials: C
authors.lastname: Munoz
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Bernhard
authors.initials: B
authors.lastname: Metzler
authors.forename: Frank
authors.initials: F
authors.lastname: Heinzel
authors.forename: Jan Wilko
authors.initials: JW
authors.lastname: Schrickel
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D064752:Atrial Remodeling; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D055724:Electrophysiological Phenomena; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D054875:Ubiquitination; D014981:Xenopus / Q000254:growth & development
chemical_list: D018031:Connexin 43; D012333:RNA, Messenger; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases