Verteporfin combined with ROCK inhibitor promotes the restoration of corneal endothelial cell dysfunction in rats.

Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE

Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.

Verteporfin*/pharmacology ; Verteporfin*/therapeutic use ; rho-Associated Kinases*/antagonists & inhibitors ; rho-Associated Kinases*/metabolism ; Rats, Sprague-Dawley*; Animals ; Rats ; Male ; Humans ; Endothelium, Corneal/drug effects ; Endothelium, Corneal/metabolism ; Endothelium, Corneal/pathology ; Amides/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; YAP-Signaling Proteins/metabolism ; Aquaporin 1/metabolism ; Aquaporin 1/antagonists & inhibitors ; Aquaporin 1/genetics ; Drug Therapy, Combination ; Photosensitizing Agents/pharmacology ; Photosensitizing Agents/therapeutic use

Corneal endothelial cells (CECs) dysfunction frequently results in a hazy, edematous cornea due to corneal endothelial decompensation and is a major cause of corneal blindness. Drug interventions provide a less invasive alternative to corneal transplantation surgery. However, endothelial-to-mesenchymal transition (EndMT) limits CECs function. Rho-kinase (ROCK) inhibitors, shown in numerous studies to be an adjunctive therapy for CECs dysfunction, cannot completely reverse pathological EndMT caused by inflammatory environmental damage. Verteporfin (VP) is an inhibitor of Yes-associated protein (YAP) and has significant inhibitory effects on cell fibrosis and mesenchymal transition. Here, we explored VP's utility in mitigating EndMT during ROCK inhibitors treatment of corneal endothelial dysfunction. We surgically constructed a rat model of CECs injury and studied VP and ROCK inhibitors' effects on EndMT, cell proliferation, and corneal edema using RNA-Seq sequencing, immunofluorescence, optical coherence tomography, and qPCR. The results indicated that YAP expression in human fetal CECs was higher than in adults and decreased with age in rats. Moreover, YAP expression in human CECs was negatively correlated with functional genes, such as AQP1 and ATP1A1. VP effectively reversed EndMT and accelerated corneal hydration regression. However, it inhibited CECs proliferation. We also confirmed that the optimal ratio of VP combined with Y-27632 (ROCK inhibitor) was 1:1, promoting CECs proliferation and reversing EndMT by down-regulating transcription factors downstream of TGF-β signaling, thereby increasing CECs functional and intercellular adhesion proteins. These combined effects promote corneal endothelial damage repair, providing a new treatment strategy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Erratum in: Biochem Pharmacol. 2024 Dec 31;232:116737. doi: 10.1016/j.bcp.2024.116737. (PMID: 39742688)

Keywords: Corneal endothelial cell dysfunction; Corneal endothelial-to-mesenchymal transition; Verteporfin; Yes-associated protein

0X9PA28K43 (Verteporfin)
EC 2.7.11.1 (rho-Associated Kinases)
0 (Amides)
0 (Yap1 protein, rat)
0 (Protein Kinase Inhibitors)
0 (Pyridines)
0 (YAP-Signaling Proteins)
146410-94-8 (Aquaporin 1)
0 (Aqp1 protein, rat)
138381-45-0 (Y 27632)
0 (Photosensitizing Agents)

Date Created: 20241121 Date Completed: 20241212 Latest Revision: 20250101

20250102

10.1016/j.bcp.2024.116641

39571917