T-Tubule Remodeling During Transition From Hypertrophy to Heart Failure
- 20 August 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 107 (4), 520-531
- https://doi.org/10.1161/circresaha.109.212324
Abstract
The transverse tubule (T-tubule) system is the ultrastructural substrate for excitation-contraction coupling in ventricular myocytes; T-tubule disorganization and loss are linked to decreased contractility in end stage heart failure (HF). We sought to examine (1) whether pathological T-tubule remodeling occurs early in compensated hypertrophy and, if so, how it evolves during the transition from hypertrophy to HF; and (2) the role of junctophilin-2 in T-tubule remodeling. We investigated T-tubule remodeling in relation to ventricular function during HF progression using state-of-the-art confocal imaging of T-tubules in intact hearts, using a thoracic aortic banding rat HF model. We developed a quantitative T-tubule power (TT(power)) index to represent the integrity of T-tubule structure. We found that discrete local loss and global reorganization of the T-tubule system (leftward shift of TT(power) histogram) started early in compensated hypertrophy in left ventricular (LV) myocytes, before LV dysfunction, as detected by echocardiography. With progression from compensated hypertrophy to early and late HF, T-tubule remodeling spread from the LV to the right ventricle, and TT(power) histograms of both ventricles gradually shifted leftward. The mean LV TT(power) showed a strong correlation with ejection fraction and heart weight to body weight ratio. Over the progression to HF, we observed a gradual reduction in the expression of a junctophilin protein (JP-2) implicated in the formation of T-tubule/sarcoplasmic reticulum junctions. Furthermore, we found that JP-2 knockdown by gene silencing reduced T-tubule structure integrity in cultured adult ventricular myocytes. T-tubule remodeling in response to thoracic aortic banding stress begins before echocardiographically detectable LV dysfunction and progresses over the development of overt structural heart disease. LV T-tubule remodeling is closely associated with the severity of cardiac hypertrophy and predicts LV function. Thus, T-tubule remodeling may constitute a key mechanism underlying the transition from compensated hypertrophy to HF.Keywords
This publication has 47 references indexed in Scilit:
- Excitation–contraction coupling changes during postnatal cardiac developmentJournal of Molecular and Cellular Cardiology, 2010
- Molecular evolution of the junctophilin gene familyPhysiological Genomics, 2009
- Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heartProceedings of the National Academy of Sciences of the United States of America, 2009
- Novel Features of the Rabbit Transverse Tubular System Revealed by Quantitative Analysis of Three-Dimensional Reconstructions from Confocal ImagesBiophysical Journal, 2008
- Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodellingCardiovascular Research, 2007
- Intermolecular Failure of L-type Ca2+ Channel and Ryanodine Receptor Signaling in HypertrophyPLoS Biology, 2007
- T‐tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarctionJournal Of Physiology-London, 2006
- Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathiesBiochemical and Biophysical Research Communications, 2004
- Chronic Pressure Overload Cardiac Hypertrophy and Failure in Guinea Pigs: II. Cytoskeletal RemodelingJournal of Molecular and Cellular Cardiology, 1999
- Quantitative electron microscopic description of heart muscle cells: Application to normal, hypertrophied and thyroxin-stimulated heartsThe American Journal of Cardiology, 1973