Simvastatin Attenuates Glucocorticoid-Induced Human Trabecular Meshwork Cell Dysfunction via YAP/TAZ Inactivation

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• Trabecular meshwork (TM) impairment increases outflow resistance in glaucoma.
• Yes-associated protein (YAP) and TAZ are implicated in TM cell dysfunction.
• The mevalonate pathway regulates YAP/TAZ activity, and statins inhibit this pathway.

Purpose of the Study:

• To investigate if simvastatin attenuates glucocorticoid-induced human TM (HTM) cell dysfunction via YAP/TAZ inactivation.
• To explore the link between statins, the mevalonate pathway, and YAP/TAZ signaling in HTM cells.

Main Methods:

• HTM cells were cultured in bioengineered extracellular matrix (ECM) hydrogels.
• Dexamethasone induced a pathologic phenotype, with or without simvastatin.
• Assessed YAP/TAZ activity, cytoskeletal organization, and ECM remodeling.

Main Results:

• Simvastatin inhibited YAP/TAZ nuclear localization and activity in HTM cells.
• Simvastatin reduced actin stress fiber formation and myosin light chain phosphorylation.
• Simvastatin attenuated dexamethasone-induced ECM stiffening and fibronectin deposition.

Conclusions:

• Simvastatin inactivates YAP/TAZ, mitigating HTM cell pathobiology in an ECM microenvironment.
• Statin use may reduce glaucoma risk through indirect YAP/TAZ inhibition.