Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000 Sungai Buloh, Selangor, Malaysia.
Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000 Sungai Buloh, Selangor, Malaysia; Center for Neuroscience Research and I-PPerForM, Universiti Teknologi MARA, Sungai Buloh Campus, 47000 Sungai Buloh, Selangor, Malaysia.
Eur J Pharmacol. 2018 Nov 5;838:1-10. doi: 10.1016/j.ejphar.2018.08.035. Epub 2018 Aug 29.
Trans-resveratrol was earlier shown to lower intraocular pressure (IOP) in rats; however, its mechanisms of action remain unclear. It has been shown to modulate adenosine receptor (AR) and TGF-β2 signaling, both of which play a role in regulating IOP. Hence, we investigated effects of trans-resveratrol on AR and TGF-β2 signaling. Steroid-induced ocular hypertensive (SIOH) rats were pretreated with AAR, phospholipase C (PLC) and ERK1/2 inhibitors and were subsequently treated with single drop of trans-resveratrol. Metalloproteinases (MMP)-2 and -9 were measured in aqueous humor (AH). In another set of experiments, effect of trans-resveratrol on AH level of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) was determined after single and multiple drop administration in SIOH rats. Effect of trans-resveratrol on ARs expression, PLC and pERK1/2 activation and MMPs, tPA and uPA secretion was determined using human trabecular meshwork cells (HTMC). Further, effect of trans-resveratrol on TGF-β2 receptors, SMAD signaling molecules and uPA and tPA expression by HTMC was determined in the presence and absence of TGF-β2. Pretreatment with AAR, PLC and ERK1/2 inhibitors antagonized the IOP lowering effect of trans-resveratrol and caused significant reduction in the AH level of MMP-2 in SIOH rats. Trans-resveratrol increased AAR and AAR expression, cellular PLC, pERK1/2 levels and MMP-2, tPA and uPA secretion by HTMC. Additionally, it produced TGFβRI downregulation and SMAD 7 upregulation. In conclusion, IOP lowering effect of trans-resveratrol involves upregulation of AAR expression, PLC and ERK1/2 activation and increased MMP-2 secretion. It downregulates TGFβRI and upregulates SMAD7 hence, inhibits TGF-β2 signaling.
反式白藜芦醇先前已被证明可降低大鼠眼内压（IOP）；然而，其作用机制尚不清楚。它已被证明可调节腺苷受体（AR）和 TGF-β2 信号，这两者在调节 IOP 中都发挥作用。因此，我们研究了反式白藜芦醇对 AR 和 TGF-β2 信号的影响。甾体诱导的高眼压（SIOH）大鼠先用 AAR、磷脂酶 C（PLC）和 ERK1/2 抑制剂预处理，然后用一滴反式白藜芦醇处理。房水中测量金属蛋白酶（MMP）-2 和 -9。在另一组实验中，在 SIOH 大鼠中单次和多次滴注后，测定反式白藜芦醇对房水中组织型纤溶酶原激活剂（tPA）和尿激酶纤溶酶原激活剂（uPA）水平的影响。用人类小梁网细胞（HTMC）测定反式白藜芦醇对 AR 表达、PLC 和 pERK1/2 激活以及 MMPs、tPA 和 uPA 分泌的影响。此外，在存在和不存在 TGF-β2 的情况下，测定了反式白藜芦醇对 HTMC 中 TGF-β2 受体、SMAD 信号分子以及 uPA 和 tPA 表达的影响。AAR、PLC 和 ERK1/2 抑制剂预处理拮抗了反式白藜芦醇的降眼压作用，并导致 SIOH 大鼠房水中 MMP-2 水平显著降低。反式白藜芦醇增加了 AR 和 AR 表达、细胞 PLC、pERK1/2 水平以及 MMP-2、tPA 和 uPA 的分泌。此外，它还产生了 TGFβRI 下调和 SMAD7 上调。总之，反式白藜芦醇的降眼压作用涉及 AR 表达、PLC 和 ERK1/2 激活的上调以及 MMP-2 分泌的增加。它下调 TGFβRI 并上调 SMAD7，从而抑制 TGF-β2 信号。
