Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1

Sarah A. Swager, Dawn A. Delfín, Neha Rastogi, Honglan Wang, Benjamin D. Canan, Vadim V. Fedorov, Peter J. Mohler, Ahmet Kilic, Robert S.D. Higgins, Mark T. Ziolo, Paul M.L. Janssen, Jill A. Rafael-Fortney

Research output: Contribution to journalArticle

Abstract

Abstract Claudin-5 is transcriptionally downregulated resulting in dramatically reduced protein levels in human heart failure. Studies in mice have demonstrated that reduced claudin-5 levels occur prior to cardiac damage and far before reduced whole heart function. Therefore, claudin-5 may be a useful early therapeutic target for human heart failure. However, the cell types in which claudin-5 is localized in human heart and from which claudin-5 is reduced in heart failure is not known. The recent identification of claudin-5's interaction with ephrin-B1 in mouse hearts has also not been investigated in non-failing or failing human hearts. In this study we collected human left ventricular mid-myocardium histological samples from 7 non-failing hearts and 16 end-stage failing hearts. Immunoblots demonstrate severe reductions of claudin-5 protein in 14 of 16 failing hearts compared to non-failing controls. Claudin-5 was observed to localize to cardiomyocytes, endothelial cells, and a subset of fibroblasts in non-failing human heart sections. In isolated cardiomyocytes, the transmembrane claudin-5 protein localized in longitudinal striations in lateral membranes. In failing heart, both cardiomyocyte and endothelial claudin-5 localization was severely reduced, but claudin-5 remained in fibroblasts. Absence of claudin-5 staining also correlated with the reduction of the endothelial cell marker CD31. Ephrin-B1 localization, but not protein levels, was altered in failing hearts supporting that claudin-5 is required for ephrin-B1 localization. These data support that loss of claudin-5 in cardiomyocytes and endothelial cells is prevalent in human heart failure. Investigating claudin-5/ephrin-B1 protein complexes and gene regulation may lead to novel therapies.

Original languageEnglish (US)
Article number6813
Pages (from-to)160-167
Number of pages8
JournalCardiovascular Pathology
Volume24
Issue number3
DOIs
StatePublished - May 1 2015
Externally publishedYes

Keywords

  • Cell junctions
  • Claudin-5
  • Ephrin-B1
  • Heart failure
  • Human heart explants
  • Human myocardium

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cardiology and Cardiovascular Medicine

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    Swager, S. A., Delfín, D. A., Rastogi, N., Wang, H., Canan, B. D., Fedorov, V. V., Mohler, P. J., Kilic, A., Higgins, R. S. D., Ziolo, M. T., Janssen, P. M. L., & Rafael-Fortney, J. A. (2015). Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1. Cardiovascular Pathology, 24(3), 160-167. [6813]. https://doi.org/10.1016/j.carpath.2014.10.006