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

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 sarco...

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Published in:Cardiovascular research 2013-05, Vol.98 (2), p.269-276
Main Authors: Zhang, Hai-Bo, Li, Rong-Chang, Xu, Ming, Xu, Shi-Ming, Lai, Ying-Si, Wu, Hao-Di, Xie, Xian-Jin, Gao, Wei, Ye, Haihong, Zhang, You-Yi, Meng, Xu, Wang, Shi-Qiang
Format: Article
Language:English
Subjects:
Aged
Calcium Signaling
Cardiomyopathy, Dilated - pathology
Excitation Contraction Coupling
Heart Failure - pathology
Humans
Membrane Proteins - physiology
MicroRNAs - physiology
Middle Aged
Myocardial Ischemia - pathology
Myocytes, Cardiac - ultrastructure
Sarcoplasmic Reticulum - ultrastructure
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Summary: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. 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. 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.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvt030