title: Plasticity of surface structures and β(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure.
abstract: BACKGROUND
  Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal β(2)-adrenergic receptors (β(2)AR) and localized secondary messenger signaling. Plasticity of these changes in the reverse remodeled failing ventricle is unknown. We used AAV9.SERCA2a gene therapy to rescue failing rat hearts and measured z-groove index, T-tubule density, and compartmentalized β(2)AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique.
  
  
  RESULTS
  Cardiomyocyte surface morphology, quantified by z-groove index and T-tubule density, was normalized in reverse-remodeled hearts after SERCA2a gene therapy. Recovery of sarcolemmal microstructure correlated with functional β(2)AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local β(2)AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of β(2)AR localization was associated with recovery of βAR-stimulated contractile responses in rescued cardiomyocytes. Retubulation was associated with reduced spatial heterogeneity of electrically stimulated calcium transients and recovery of myocardial BIN-1 and TCAP protein expression but not junctophilin-2.
  
  
  CONCLUSIONS
  In summary, abnormalities of sarcolemmal structure in heart failure show plasticity with reappearance of z-grooves and T-tubules in reverse-remodeled hearts. Recovery of surface topology is necessary for normalization of β(2)AR location and signaling responses.
authors.affiliation: Myocardial Function Unit, National Heart and Lung Institute, Imperial College, London, United Kingdom. a.lyon@ic.ac.uk
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Michele
authors.initials: M
authors.lastname: Miragoli
authors.forename: Markus B
authors.initials: MB
authors.lastname: Sikkel
authors.forename: Helen
authors.initials: H
authors.lastname: Paur
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Peters
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Korchev
authors.forename: Ken T
authors.initials: KT
authors.lastname: Macleod
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D031541:Fluorescence Resonance Energy Transfer; D015316:Genetic Therapy; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D023421:Models, Animal; D009124:Muscle Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D012508:Sarcolemma / Q000473:pathology* / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530914:Bin1 protein, rat; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D018343:Receptors, Adrenergic, beta-2; C507454:Tcap protein, rat; D025521:Tumor Suppressor Proteins; D000242:Cyclic AMP; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases