Ultrastructural remodelling of Ca 2+ signalling apparatus in failing heart cells

摘要

Aims The contraction of a heart cell is controlled by Ca 2+-induced Ca 2+ release between L-type Ca 2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCCRyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCCRyR signalling and contractility. Methods and resultsIn rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TTSR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TTSR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca 2+ release activation. ConclusionsThe shrinking and eventual absence of TTSR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca 2+ release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TTSR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies.