Increased collagen within the transverse tubules in human heart failure

David J. Crossman, Xin Shen, Mia Jüllig, Michelle Munro, Yufeng Hou, Martin Middleditch, Darshan Shrestha, Amy Li, Sean Lal, Cristobal G. Dos Remedios, David Baddeley, Peter N. Ruygrok, Christian Soeller

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Aims In heart failure transverse-tubule (t-tubule) remodelling disrupts calcium release, and contraction.T-tubules in human failing hearts exhibit increased labelling by wheat germ agglutinin (WGA), a lectin that binds to the dystrophin-associated glycoprotein complex.We hypothesized changes in this complex may explain the increased WGA labelling and contribute to t-tubule remodelling in the failing human heart.In this study we sought to identify the molecules responsible for this increased WGA labelling.Methods and results Confocal and super-resolution fluorescence microscopy and proteomic analyses were used to quantify left ventricle samples from healthy donors and patients with idiopathic dilated cardiomyopathy (IDCM).Confocal microscopy demonstrated both WGA and dystrophin were located at t-tubules.Super-resolution microscopy revealed that WGA labelling of t-tubules is largely located within the lumen while dystrophin was restricted to near the sarcolemma.Western blots probed with WGA reveal a 5.7-fold increase in a 140 kDa band in IDCM.Mass spectrometry identified this band as type VI collagen (Col-VI) comprised of a1(VI), a2(VI), and a3(VI) chains.Pertinently, mutations in Col-VI cause muscular dystrophy.Western blotting identified a 2.4-fold increased expression and 3.2-fold increased WGA binding of Col-VI in IDCM.Confocal images showed that Col-VI is located in the t-tubules and that their diameter increased in the IDCM samples.Super-resolution imaging revealed Col-VI was restricted to the t-tubule lumen where increases were associated with displacement in the sarcolemma as identified from dystrophin labelling.Samples were also labelled for type I, III, and IV collagen.Both confocal and super-resolution imaging identified that these collagens were also present within t-tubule lumen.Conclusion Increased expression and labelling of collagen in IDCM samples indicates fibrosis may contribute to t-tubule remodelling in human heart failure.All rights reserved.

Original languageEnglish
Pages (from-to)879-891
Number of pages13
JournalCardiovascular Research
Volume113
Issue number8
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Keywords

  • Human heart failure
  • Idiopathic dilated cardiomyopathy
  • Superresolution
  • Transverse tubules
  • Type VI collagen

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