Activation of the ROCK/MYLK Pathway Affects Complex Molecular and Morphological Changes of the Trabecular Meshwork Associated With Ocular Hypertension.

Autor:	Hsu CC; Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Lin FP; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan., Tseng HC; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan., Ho PK; School of Dentistry, National Defense Medical Center, Taipei, Taiwan., Chen YH; Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan., Chen YG; Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Lu DW; Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Chen YH; Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Chou JL; Department of Research and Development, National Defense Medical Center, Taipei, Taiwan., Chen HC; Department of Research and Development, National Defense Medical Center, Taipei, Taiwan., Huang YC; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.; Department of Research and Development, National Defense Medical Center, Taipei, Taiwan.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2024 Aug 01; Vol. 65 (10), pp. 17.
DOI:	10.1167/iovs.65.10.17
Abstrakt:	Purpose: The Rho-associated protein kinase and myosin light chain kinase (ROCK/MYLK) pathway undeniably plays a pivotal role in the pathophysiology of primary open-angle glaucoma (POAG). In our study, we utilized both ocular hypertension (OHT) rabbit models and clinical investigations to gain invaluable insights that propel the development of novel treatments targeting proteins and genes associated with the trabecular meshwork (TM), thereby offering promising avenues for the management of POAG. Methods: Following microbead injections into the anterior chamber of the ocular cavity of rabbits, we observed elevated histiocyte numbers and immune scores for MYLK-4/ pMLC-2, alongside a reduction in the void space within the TM. Notably, treatment was performed with 0.1% ITRI-E-(S)-4046, a compound with dual kinase inhibitor (highly specific inhibitor of ROCK1/2 and MYLK4), significantly reduced intraocular pressure (IOP; P < 0.05) and expanded the void space within the TM (P < 0.0001) compared with OHT rabbits. In clinical investigations, we utilized whole transcriptome sequencing to analyze gene expression specifically related to the TM, obtained from patients (5 early-onset and 5 late-onset) undergoing trabeculectomy. Results: Our findings revealed 103 differential expression genes (DEGs) out of 265 molecules associated with the Rho family GTPase pathway, exhibiting a P value of 1.25E-10 and a z-score of -2.524. These results underscore significant differences between the early-onset and late-onset POAG and highlight the involvement of the ROCK/MYLK pathway. Conclusions: These findings underscore the critical involvement of the ROCK/MYLK pathway in both OHT-related and different onsets of POAG, providing valuable insights into the TM-related molecular mechanisms underlying the disease.
Databáze:	MEDLINE
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