title: Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1.
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.
authors.affiliation: Dept. of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH 43210.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Swager
authors.affiliation: Dept. of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH 43210.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Delfín
authors.affiliation: Dept. of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH 43210.|Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Neha
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Honglan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Dept. of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Dept. of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Robert S D
authors.initials: RSD
authors.lastname: Higgins
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ziolo
authors.affiliation: Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Paul M L
authors.initials: PML
authors.lastname: Janssen
authors.affiliation: Dept. of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH 43210.|Dept. of Physiology & Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.|Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D062507:Claudin-5 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D036387:Ephrin-B1 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; C484288:EFNB1 protein, human; D036387:Ephrin-B1
keywords: Cell junctions; Claudin-5; Ephrin-B1; Heart failure; Human heart explants; Human myocardium