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Article

The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner

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Virginia Tech, Translational Biology Medicine and Health (TBMH) Program, Roanoke, VA 24016, USA
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Department of Biomedical Engineering, College of Engineering, The Ohio State University, 460 Medical Center Dr., Rm 415A, IBMR, Columbus, OH 43210, USA
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The Frick Center for Heart Failure and Arrhythmia, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
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Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA 24016, USA
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Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
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Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Maliha Zahid
Biomolecules 2021, 11(8), 1192; https://doi.org/10.3390/biom11081192
Received: 16 July 2021 / Revised: 1 August 2021 / Accepted: 6 August 2021 / Published: 12 August 2021
(This article belongs to the Section Biological Factors)
The Cx43 carboxyl-terminus (CT) mimetic peptide, αCT1, originally designed to bind to Zonula Occludens 1 (ZO1) and thereby inhibit Cx43/ZO1 interaction, was used as a tool to probe the role of Cx43/ZO1 association in regulation of epithelial/endothelial barrier function. Using both in vitro and ex vivo methods of barrier function measurement, including Electric Cell-Substrate Impedance Sensing (ECIS), a TRITC-dextran Transwell permeability assay, and a FITC-dextran cardiovascular leakage protocol involving Langendorff-perfused mouse hearts, αCT1 was found to protect the endothelium from thrombin-induced breakdown in cell–cell contacts. Barrier protection was accompanied by significant remodeling of the F-actin cytoskeleton, characterized by a redistribution of F-actin away from the cytoplasmic and nuclear regions of the cell, towards the endothelial cell periphery, in association with alterations in cellular chiral orientation distribution. In line with observations of increased cortical F-actin, αCT1 upregulated cell–cell border localization of endothelial VE-cadherin, the tight junction protein Zonula Occludens 1 (ZO1), and the Gap Junction Protein (GJ) Connexin43 (Cx43). A ZO1 binding-incompetent variant of αCT1, αCT1-I, indicated that these effects on barrier function and barrier-associated proteins, were likely associated with Cx43 CT sequences retaining ability to interact with ZO1. These results implicate the Cx43 CT and its interaction with ZO1, in the regulation of endothelial barrier function, while revealing the therapeutic potential of αCT1 in the treatment of vascular edema. View Full-Text
Keywords: Cx43; Zonula Occludens 1; barrier function; tight junctions; adherens junctions; actin cytoskeleton; endothelial cells Cx43; Zonula Occludens 1; barrier function; tight junctions; adherens junctions; actin cytoskeleton; endothelial cells
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MDPI and ACS Style

Strauss, R.E.; Mezache, L.; Veeraraghavan, R.; Gourdie, R.G. The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner. Biomolecules 2021, 11, 1192. https://doi.org/10.3390/biom11081192

AMA Style

Strauss RE, Mezache L, Veeraraghavan R, Gourdie RG. The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner. Biomolecules. 2021; 11(8):1192. https://doi.org/10.3390/biom11081192

Chicago/Turabian Style

Strauss, Randy E., Louisa Mezache, Rengasayee Veeraraghavan, and Robert G. Gourdie. 2021. "The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner" Biomolecules 11, no. 8: 1192. https://doi.org/10.3390/biom11081192

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