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

Abstract:

AIMS: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. METHODS AND 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. CONCLUSION: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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Zhang HB,Li RC,Xu M,Xu SM,Lai YS,Wu HD,Xie XJ,Gao W,Ye H,Zhang YY,Meng X,Wang SQ

doi

10.1093/cvr/cvt030

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

269-76

issue

2

eissn

0008-6363

issn

1755-3245

pii

cvt030

journal_volume

98

pub_type

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