title: Corneal antifibrotic switch identified in genetic and pharmacological deficiency of vimentin.
abstract: The type III intermediate filaments (IFs) are essential cytoskeletal elements of mechanosignal transduction and serve critical roles in tissue repair. Mice genetically deficient for the IF protein vimentin (Vim(-/-)) have impaired wound healing from deficits in myofibroblast development. We report a surprising finding made in Vim(-/-) mice that corneas are protected from fibrosis and instead promote regenerative healing after traumatic alkali injury. This reparative phenotype in Vim(-/-) corneas is strikingly recapitulated by the pharmacological agent withaferin A (WFA), a small molecule that binds to vimentin and down-regulates its injury-induced expression. Attenuation of corneal fibrosis by WFA is mediated by down-regulation of ubiquitin-conjugating E3 ligase Skp2 and up-regulation of cyclin-dependent kinase inhibitors p27(Kip1) and p21(Cip1). In cell culture models, WFA exerts G(2)/M cell cycle arrest in a p27(Kip1)- and Skp2-dependent manner. Finally, by developing a highly sensitive imaging method to measure corneal opacity, we identify a novel role for desmin overexpression in corneal haze. We demonstrate that desmin down-regulation by WFA via targeting the conserved WFA-ligand binding site shared among type III IFs promotes further improvement of corneal transparency without affecting cyclin-dependent kinase inhibitor levels in Vim(-/-) mice. This dissociates a direct role for desmin in corneal cell proliferation. Taken together, our findings illuminate a previously unappreciated pathogenic role for type III IF overexpression in corneal fibrotic conditions and also validate WFA as a powerful drug lead toward anti-fibrosis therapeutic development.
authors: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors: Paola
authors: P
authors: Bargagna-Mohan
authors: Riya R
authors: RR
authors: Paranthan
authors: Adel
authors: A
authors: Hamza
authors: Chang-Guo
authors: CG
authors: Zhan
authors: Do-Min
authors: DM
authors: Lee
authors: Kyung Bo
authors: KB
authors: Kim
authors: Daniel L
authors: DL
authors: Lau
authors: Cidambi
authors: C
authors: Srinivasan
authors: Keiko
authors: K
authors: Nakayama
authors: Keiichi I
authors: KI
authors: Nakayama
authors: Harald
authors: H
authors: Herrmann
authors: Royce
authors: R
authors: Mohan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003315:Cornea / Q000378:metabolism* / Q000473:pathology; D003316:Corneal Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054358:Withanolides / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000235:genetics
chemical_list: D003893:Desmin; D044786:S-Phase Kinase-Associated Proteins; D014746:Vimentin; D054358:Withanolides; C009684:withaferin A