Atorvastatin reduces IOP in ocular hypertension in vivo and suppresses ECM in trabecular meshwork perhaps via FGD4

Abstract

To explore the role of atorvastatin in regulating intraocular pressure (IOP) in glaucoma in vivo , and to investigate its related molecular pathway in vitro , an ocular hypertension model was generated by intravitreal injection of an adenoviral vector encoding transforming growth factor (TGF)-β2 in the right eye of BALB/cJ mice, while the left was treated with an empty control adenovirus. To determine its anti-intraocular hypertension role, these induced hyper-IOP mice were gavaged with atorvastatin (20 mg/kg/day). Furthermore, extracellular matrix (ECM) factors were examined in the primary human trabecular meshwork (HTM) cells followed atorvastatin (0~200 µ M) treatment in vitro . Whole genome microarray was employed to identify potential therapeutic target molecules associated with ECM regulation. Unilateral murine ocular hypertension was induced, via intravitreal injection of the adenoviral vector carrying the human TGF-β2 gene (Ad.hTGF-β2 226/228 ), raising IOP from 12±1.6 to 32.3±0.7 mmHg (n=6, P<0.05) at day 15, which plateaued from day 15 to 30. Atorvastatin administration from day 15 to 30 decreased IOP from 32.3±0.7 to 15.4±1.1 mmHg (n=6, P<0.05) at day 30. Additionally, atorvastatin administration changed the morphology of cultured HTM cells from an elongated and adherent morphology into rounded, less elongated and less adherent cells, accompanied with suppressed expression of ECM. Gene Ontology and Genome analysis revealed that FGD4 (FYVE, RhoGEF and PH domain containing 4) might be a key factor contributing to these changes. Our data demonstrated that atorvastatin reduced TGF-β2-induced ocular hypertension in vivo , perhaps via modifying cellular structure and decreasing ECM, using the FGD4 signaling pathway, as demonstrated in HTM cells. Our findings provide some useful information for the management of glaucoma, with statin therapy revealing a potential novel therapeutic pathway for glaucoma treatment.

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

“…38,100,101 The proposed mechanism for statins to decrease IOP is by inhibiting the isoprenylation of Rho GTPase thus resulting in decreased actomyosin contractile activity and ECM synthesis/assembly. 39,[102][103][104] All these studies imply that there is an association between lipids, ocular hypertension, and POAG. The data we show clearly suggest that inactivating the SCAP-SREBP pathway decreases TM lipids.…”

“…Interestingly, even though it is not clear how cholesterol is related to the glaucoma risk, there is mounting evidence showing that HMG‐CoA reductase inhibitor statin can decrease POAG risk by mitigating disease progression 38,100,101 . The proposed mechanism for statins to decrease IOP is by inhibiting the isoprenylation of Rho GTPase thus resulting in decreased actomyosin contractile activity and ECM synthesis/assembly 39,102‐104 . All these studies imply that there is an association between lipids, ocular hypertension, and POAG.…”

YAP/TAZ inactivation with simvastatin attenuates glucocorticoid-induced human trabecular meshwork cell dysfunction

“…By the same token, lovastatin was shown to cause marked changes in human TM cell morphology including a loss of filamentous (F)-actin stress fiber organization 35 , concomitant with a marked accumulation of cytosolic inactive Rho GTPase proteins 36 . Atorvastatin, another lipophilic statin with higher potency compared to lovastatin 37 , was found to reduce ECM protein expression in human TM cells 38 , as well as induce significant changes in cellular morphology and focal adhesions 39 . Importantly, it was shown that YAP/TAZ activity is controlled by the mevalonate pathway.…”

Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation

“…Interestingly, even though it is not clear how cholesterol is related to the glaucoma risk, there is mounting evidence showing that HMG-CoA reductase inhibitor statin can decrease POAG risk by mitigating disease progression (35,86,87). The proposed mechanism for statins to decrease IOP is by inhibiting the isoprenylation of Rho GTPase thus resulting in decreased actomyosin contractile activity and ECM synthesis/assembly (36,(88)(89)(90). All these studies imply that there is an association between lipids, ocular hypertension, and POAG.…”