Abstract
Transforming growth factor-beta 2 (TGF-β2) is highly concentrated in the aqueous humor of primary open-angle glaucoma patients. TGF-β2 causes fibrosis of outflow tissues, such as the trabecular meshwork (TM), and increases intraocular pressure by increasing resistance to aqueous humor outflow. Recently, histone deacetylase (HDAC) activity was investigated in fibrosis in various tissues, revealing that HDAC inhibitors suppress tissue fibrosis. However, the effect of HDAC inhibitors on fibrosis in the eye was not determined. Here, we investigated the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on TGF-β2-induced increased resistance to aqueous humor outflow. We found that SAHA suppressed TGF-β2-induced outflow resistance in perfused porcine eyes. Moreover, SAHA cotreatment suppressed TGF-β2-induced ocular hypertension in rabbits. The permeability of monkey TM (MTM) and Schlemm’s canal (MSC) cell monolayers was decreased by TGF-β2 treatment. SAHA inhibited the effects of TGF-β2 on the permeability of these cells. TGF-β2 also increased the expression of extracellular matrix proteins (fibronectin and collagen type I or IV) in MTM, MSC, and human TM (HTM) cells, while SAHA inhibited TGF-β2-induced extracellular matrix protein expression in these cells. SAHA also inhibited TGF-β2-induced phosphorylation of Akt and ERK, but did not inhibit Smad2/3 phosphorylation, the canonical pathway of TGF-β signaling. Moreover, SAHA induced the expression of phosphatase and tensin homolog, a PI3K/Akt signaling factor, as well as bone morphogenetic protein 7, an endogenous antagonist of TGF-β. These results imply that SAHA prevents TGF-β2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-β signaling in TM and MSC cells.
Highlights
Glaucoma, a major cause of blindness worldwide [1], is a multifactorial disorder [2, 3] in which elevated intraocular pressure (IOP) is a major risk factor [4, 5]
We evaluated the effects of suberoylanilide hydroxamic acid (SAHA), an Histone deacetylase (HDAC) inhibitor, on transforming growth factor-beta 2 (TGF-β2)-induced outflow resistance using organ culture perfusion of a porcine eye
We examined the effect of SAHA on TGF-β2-induced ocular hypertension in rabbits
Summary
We evaluated the effects of SAHA, an HDAC inhibitor, on TGF-β2-induced outflow resistance using organ culture perfusion of a porcine eye. Simultaneous treatment with TGF-β2 and SAHA significantly suppressed TGF-β2-induced TEER elevation in MTM and MSC cells (Fig. 2, B and D). In MTM cells, TGF-β2 increased the expression of fibronectin and collagen type I, and SAHA suppressed this TGF-β2-induced elevation (Fig. 4, A–C). Expression of α-SMA protein was significantly increased by TGF-β2 treatment, and SAHA suppressed the TGF-β2-induced α-SMA expression in HTM cells (Fig. 4I). In MTM and HTM cells, simultaneous treatment with TGF-β2 and SAHA significantly increased PTEN expression at 24 h after treatment (Fig. 12, A and C). In MSC cells, both SAHA alone and simultaneous treatment with TGFβ2 significantly increased PTEN expression at 24 h after treatment, and these effects were sustained for 72 h (Fig. 12, B and E).
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