Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure

Hai Bo Zhang, Rong Chang Li, Ming Xu, Shi Ming Xu, Ying Si Lai, Hao Di Wu, Xian Jin Xie, Wei Gao, Haihong Ye, You Yi Zhang, Xu Meng, Shi Qiang Wang

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

AimsChronic heart failure is a complex clinical syndrome with impaired myocardial contractility. In failing cardiomyocytes, decreased signalling efficiency between the L-type Ca2+ channels (LCCs) in the plasma membrane (including transverse tubules, TTs) and the ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) underlies the defective excitation- contraction (E-C) coupling. It is therefore intriguing to know how the LCC-RyR signalling apparatus is remodelled in human heart failure.Methods and resultsStereological analysis of transmission electron microscopic images showed that the volume densities and the surface areas of TTs and junctional SRs were both decreased in heart failure specimens of dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). The TT-SR junctions were reduced by ∼60%, with the remaining displaced from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was reduced by ∼17% in both DCM and ICM tissues. In accordance with these remodelling, junctophilin-2 (JP2), a structural protein anchoring SRs to TTs, was down-regulated, and miR-24, a microRNA that suppresses JP2 expression, was up-regulated in both heart failure tissues.ConclusionHuman heart failure of distinct causes shared similar physical uncoupling between TTs and SRs, which appeared attributable to the reduced expression of JP2 and increased expression of miR-24. Therapeutic strategy against JP2 down-regulation would be expected to protect patients from cardiac E-C uncoupling.

Original languageEnglish (US)
Pages (from-to)269-276
Number of pages8
JournalCardiovascular Research
Volume98
Issue number2
DOIs
StatePublished - May 1 2013

Keywords

  • Ca signalling
  • Excitation-contraction coupling
  • Heart failure
  • Myocardial remodelling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Zhang, H. B., Li, R. C., Xu, M., Xu, S. M., Lai, Y. S., Wu, H. D., Xie, X. J., Gao, W., Ye, H., Zhang, Y. Y., Meng, X., & Wang, S. Q. (2013). Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure. Cardiovascular Research, 98(2), 269-276. https://doi.org/10.1093/cvr/cvt030