title: Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure.
abstract: OBJECTIVE
  Chronic heart failure is a complex clinical syndrome with impaired myocardial contractility. In failing cardiomyocytes, decreased signalling efficiency between the L-type Ca(2+) 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.
  
  
  RESULTS
  Stereological 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.
  
  
  CONCLUSIONS
  Human 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.
authors: Beijing Anzhen Hospital, Capital Medical University, Beijing 100092, China.
authors: Hai-Bo
authors: HB
authors: Zhang
authors: Rong-Chang
authors: RC
authors: Li
authors: Ming
authors: M
authors: Xu
authors: Shi-Ming
authors: SM
authors: Xu
authors: Ying-Si
authors: YS
authors: Lai
authors: Hao-Di
authors: HD
authors: Wu
authors: Xian-Jin
authors: XJ
authors: Xie
authors: Wei
authors: W
authors: Gao
authors: Haihong
authors: H
authors: Ye
authors: You-Yi
authors: YY
authors: Zhang
authors: Xu
authors: X
authors: Meng
authors: Shi-Qiang
authors: SQ
authors: Wang
mesh_terms: D000368:Aged; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000473:pathology; D056966:Excitation Contraction Coupling; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000473:pathology; D032383:Myocytes, Cardiac / Q000648:ultrastructure*; D012519:Sarcoplasmic Reticulum / Q000648:ultrastructure*
chemical_list: C543845:MIRN24 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C412507:junctophilin