Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9.
Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9.
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DOI：
10.3390/ijms221810095
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发表时间：
2021-09-18
影响因子：
5.6
通讯作者：
Zode GS
中科院分区：
文献类型：
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作者：
Maddineni P;Kasetti RB;Kodati B;Yacoub S;Zode GS
眼高压（OHT）是广泛使用的糖皮质激素（GC）治疗的严重不良反应，如果不及时诊断，可导致青光眼和完全失明。之前，我们已经证明了小的化学伴侣，4-苯基丁酸钠（PBA），通过减少眼内质网（ER）应激来拯救gc诱导的OHT。然而，PBA如何拯救gc诱导的OHT的确切机制尚不完全清楚。小梁网（TM）是由嵌入细胞外基质（ECM）内的TM细胞组成的滤过器样特化收缩组织，通过不断调节房水（AH）流出来控制眼压（IOP）。TM中异常ECM沉积的诱导是gc诱导OHT的一个标志。本研究采用气相色谱诱导OHT小鼠模型、体外培养的人TM组织和原代人TM细胞，研究PBA是否通过降解TM中异常ECM沉积来减少气相色谱诱导的OHT。我们发现，局部滴入PBA（1%）可显著降低gc诱导OHT小鼠模型的IOP升高。重要的是，PBA可以阻止TM中gc诱导的ECM的合成和沉积。我们首次报道了PBA可以通过诱导基质金属蛋白酶（MMP）9的表达和活性来降解正常人TM细胞/组织中存在的异常ECM。此外，化学抑制剂（二甲胺四环素）对MMPs活性的抑制消除了PBA对ECM还原及其相关内质网应激的影响。我们的研究表明，PBA的非伴侣活性通过激活MMP9来降解TM中异常的ECM积累。
Ocular hypertension (OHT) is a serious adverse effect of the widely prescribed glucocorticoid (GC) therapy and, if left undiagnosed, it can lead to glaucoma and complete blindness. Previously, we have shown that the small chemical chaperone, sodium-4-phenylbutyrate (PBA), rescues GC-induced OHT by reducing ocular endoplasmic reticulum (ER) stress. However, the exact mechanism of how PBA rescues GC-induced OHT is not completely understood. The trabecular meshwork (TM) is a filter-like specialized contractile tissue consisting of TM cells embedded within extracellular matrix (ECM) that controls intraocular pressure (IOP) by constantly regulating aqueous humor (AH) outflow. Induction of abnormal ECM deposition in TM is a hallmark of GC-induced OHT. Here, we investigated whether PBA reduces GC-induced OHT by degrading abnormal ECM deposition in TM using mouse model of GC-induced OHT, ex vivo cultured human TM tissues and primary human TM cells. We show that topical ocular eye drops of PBA (1%) significantly lowers elevated IOP in mouse model of GC-induced OHT. Importantly, PBA prevents synthesis and deposition of GC-induced ECM in TM. We report for the first time that PBA can degrade existing abnormal ECM in normal human TM cells/tissues by inducing matrix metalloproteinase (MMP)9 expression and activity. Furthermore, inhibition of MMPs activity by chemical-inhibitor (minocycline) abrogated PBA’s effect on ECM reduction and its associated ER stress. Our study indicates a non-chaperone activity of PBA via activation of MMP9 that degrades abnormal ECM accumulation in TM.
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影响因子：
13.7
作者：
Li T;Lindsley K;Rouse B;Hong H;Shi Q;Friedman DS;Wormald R;Dickersin K
通讯作者：
Dickersin K
影响因子：
3.9
作者：
El-Shabrawi, Y;Eckhardt, M;Ardjomand, N
通讯作者：
Ardjomand, N
影响因子：
15.1
作者：
Maddineni, Prabhavathi;Kasetti, Ramesh B.;Zode, Gulab S.
通讯作者：
Zode, Gulab S.
影响因子：
3.9
作者：
Kersey, JP;Broadway, DC
通讯作者：
Broadway, DC
影响因子：
--
作者：
ARMALY, MF
通讯作者：
ARMALY, MF