Potent inhibition of cicatricial contraction in proliferative vitreoretinal diseases by statins.
OBJECTIVE
Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.


METHODS
Human vitreous concentrations of transforming growth factor-beta2 (TGF-beta2) were measured by enzyme-linked immunosorbent assay. TGF-beta2-and vitreous-dependent phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase pathway, and collagen gel contraction simulating cicatrical contraction were analyzed using cultured hyalocytes. Inhibitory effects of simvastatin on cicatrical contraction were assessed both in vitro and in vivo.


RESULTS
Human vitreous concentrations of TGF-beta2 were significantly higher in the samples from patients with PVD compared with those without PVD. Simvastatin inhibited TGF-beta2-dependent MLC phosphorylation and gel contraction in a dose- and time-dependent manner and was capable of inhibiting translocation of Rho protein to the plasma membrane in the presence of TGF-beta2. Vitreous samples from patients with PVD enhanced MLC phosphorylation and gel contraction, whereas simvastatin almost completely inhibited these phenomena. Finally, intravitreal injection of simvastatin dose-dependently prevented the progression of diseased states in an in vivo model of PVR.


CONCLUSIONS
Statins might have therapeutic potential in the prevention of PVDs.
Kawahara
Shuhei
S
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
Hata
Yasuaki
Y
Kita
Takeshi
T
Arita
Ryoichi
R
Miura
Muneki
M
Nakao
Shintaro
S
Mochizuki
Yasutaka
Y
Enaida
Hiroshi
H
Kagimoto
Tadahisa
T
Goto
Yoshinobu
Y
Hafezi-Moghadam
Ali
A
Ishibashi
Tatsuro
T
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D018994:Myosin Light Chains / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D019821:Simvastatin / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism / Q000517:prevention & control; D014822:Vitreous Body / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D000960:Hypolipidemic Agents; D018994:Myosin Light Chains; D053781:Transforming Growth Factor beta2; D003094:Collagen; D019821:Simvastatin; D020741:rho GTP-Binding Proteins