Conditional deficiency of Rho-associated kinases disrupts endothelial cell junctions and impairs respiratory function in adult mice.

Autor: Akamine T; Department of Pharmacology, Faculty of Medicine, Oita University, Yufu, Japan., Terabayashi T; Department of Pharmacology, Faculty of Medicine, Oita University, Yufu, Japan., Sasaki T; Department of Pharmacology, Faculty of Medicine, Oita University, Yufu, Japan., Hayashi R; Department of Pharmacology, Faculty of Medicine, Oita University, Yufu, Japan., Abe I; Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan., Hirayama F; Department of Respiratory Medicine and Infectious Diseases, Faculty of Medicine, Oita University, Yufu, Japan., Nureki SI; Department of Respiratory Medicine and Infectious Diseases, Faculty of Medicine, Oita University, Yufu, Japan., Ikawa M; Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Suita, Japan., Miyata H; Department of Experimental Genome Research, Research Institute for Microbial Diseases, Suita, Japan., Tokunaga A; Division of Laboratory Animal Resources, Life Science Research Laboratory, University of Fukui, Eiheiji-cho, Japan., Kobayashi T; Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Japan.; Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Yufu, Japan., Hanada K; Clinical Engineering Research Center, Faculty of Medicine, Oita University, Yufu, Japan., Thumkeo D; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan., Narumiya S; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan., Ishizaki T; Department of Pharmacology, Faculty of Medicine, Oita University, Yufu, Japan.
Jazyk: angličtina
Zdroj: FEBS open bio [FEBS Open Bio] 2024 Jun; Vol. 14 (6), pp. 906-921. Date of Electronic Publication: 2024 Apr 11.
DOI: 10.1002/2211-5463.13802
Abstrakt: The Ras homology (Rho) family of GTPases serves various functions, including promotion of cell migration, adhesion, and transcription, through activation of effector molecule targets. One such pair of effectors, the Rho-associated coiled-coil kinases (ROCK1 and ROCK2), induce reorganization of actin cytoskeleton and focal adhesion through substrate phosphorylation. Studies on ROCK knockout mice have confirmed that ROCK proteins are essential for embryonic development, but their physiological functions in adult mice remain unknown. In this study, we aimed to examine the roles of ROCK1 and ROCK2 proteins in normal adult mice. Tamoxifen (TAM)-inducible ROCK1 and ROCK2 single and double knockout mice (ROCK1 flox/flox and/or ROCK2 flox/flox ;Ubc-CreERT2) were generated and administered a 5-day course of TAM. No deaths occurred in either of the single knockout strains, whereas all of the ROCK1/ROCK2 double conditional knockout mice (DcKO) had died by Day 11 following the TAM course. DcKO mice exhibited increased lung tissue vascular permeability, thickening of alveolar walls, and a decrease in percutaneous oxygen saturation compared with noninducible ROCK1/ROCK2 double-floxed control mice. On Day 3 post-TAM, there was a decrease in phalloidin staining in the lungs in DcKO mice. On Day 5 post-TAM, immunohistochemical analysis also revealed reduced staining for vascular endothelial (VE)-cadherin, β-catenin, and p120-catenin at cell-cell contact sites in vascular endothelial cells in DcKO mice. Additionally, VE-cadherin/β-catenin complexes were decreased in DcKO mice, indicating that ROCK proteins play a crucial role in maintaining lung function by regulating cell-cell adhesion.
(© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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