Abstract
Background-Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal-2-adrenergic receptors (2AR) 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-2AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Methods and 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 2AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local 2AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of 2AR localization was associated with recovery of AR-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 2AR location and signaling responses.
| Original language | English |
|---|---|
| Pages (from-to) | 357-365 |
| Number of pages | 9 |
| Journal | Circulation: Heart Failure |
| Volume | 5 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - May 2012 |
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Keywords
- 2-adrenergic receptors
- Excitation-contraction coupling
- Heart failure
- Remodeling heart failure
- SERCA2a gene therapy
- Transverse tubules
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Medicine(all)
Cite this
Plasticity of surface structures and 2-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure. / Lyon, Alexander R.; Nikolaev, Viacheslav O.; Miragoli, Michele; Sikkel, Markus B.; Paur, Helen; Benard, Ludovic; Hulot, Jean Sebastien; Kohlbrenner, Erik; Hajjar, Roger J.; Peters, Nicholas S.; Korchev, Yuri E.; MacLeod, Ken T.; Harding, Sian E.; Gorelik, Julia.
In: Circulation: Heart Failure, Vol. 5, No. 3, 05.2012, p. 357-365.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Plasticity of surface structures and 2-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure
AU - Lyon, Alexander R.
AU - Nikolaev, Viacheslav O.
AU - Miragoli, Michele
AU - Sikkel, Markus B.
AU - Paur, Helen
AU - Benard, Ludovic
AU - Hulot, Jean Sebastien
AU - Kohlbrenner, Erik
AU - Hajjar, Roger J.
AU - Peters, Nicholas S.
AU - Korchev, Yuri E.
AU - MacLeod, Ken T.
AU - Harding, Sian E.
AU - Gorelik, Julia
PY - 2012/5
Y1 - 2012/5
N2 - Background-Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal-2-adrenergic receptors (2AR) 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-2AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Methods and 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 2AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local 2AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of 2AR localization was associated with recovery of AR-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 2AR location and signaling responses.
AB - Background-Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal-2-adrenergic receptors (2AR) 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-2AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Methods and 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 2AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local 2AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of 2AR localization was associated with recovery of AR-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 2AR location and signaling responses.
KW - 2-adrenergic receptors
KW - Excitation-contraction coupling
KW - Heart failure
KW - Remodeling heart failure
KW - SERCA2a gene therapy
KW - Transverse tubules
UR - http://www.scopus.com/inward/record.url?scp=84864320581&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864320581&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.111.964692
DO - 10.1161/CIRCHEARTFAILURE.111.964692
M3 - Article
VL - 5
SP - 357
EP - 365
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
SN - 1941-3297
IS - 3
ER -