title: Role of RyR2 phosphorylation at S2814 during heart failure progression.
abstract: BACKGROUND
  Increased activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca(2+) leak is unclear.
  
  
  OBJECTIVE
  Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF.
  
  
  RESULTS
  Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca(2+) leak and improved sarcoplasmic reticulum Ca(2+) loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction.
  
  
  CONCLUSIONS
  Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca(2+) leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Natale
authors.initials: N
authors.lastname: Rolim
authors.forename: Sayali S
authors.initials: SS
authors.lastname: Dixit
authors.forename: Angela
authors.initials: A
authors.lastname: deAlmeida
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: William S
authors.initials: WS
authors.lastname: Lawrence
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.forename: Kristine
authors.initials: K
authors.lastname: Skårdal
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Xun
authors.initials: X
authors.lastname: Ai
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pogwizd
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000328:Adult; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012694:Serine; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D047428:Protein Kinase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D012694:Serine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2