Wang Haiyan, Liu Xuyang, Guo Lin, Gabelt Bi'Ann T, Lee Ping-Yu, Podos Steven M, Wang Ningli, Kaufman Paul L
Tongren Ophthalmic Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People's Republic of China.
Curr Eye Res. 2007 Oct;32(10):843-50. doi: 10.1080/02713680701585880.
To determine the effects of misakinolide (MISA) A, which leads to the disassembly of actin filaments, on the actin cytoskeleton of cultured human trabecular meshwork (HTM) cells and on intraocular pressure (IOP) in living rats and monkeys.
Cultured HTM cells were treated with MISA A, and the changes in the actin cytoskeleton were determined by immunofluorescence microscopy. Elevated IOP was induced in cynomolgus monkeys by unilateral laser photocoagulation of the trabecular meshwork (TM). The IOP response after topical administration of MISA A was determined in normotensive rats (Tonopen) and glaucomatous monkeys (pneumotonometer and Tonopen) at 0.5, 1, 2, 3, 4, 5, and 6 hr.
MISA A caused dose- and time-dependent disruption of actin stress fibers in cultured HTM cells. Actin microfilaments and vinculin containing focal contacts deteriorated after 2 hr, 30 and 10 min of incubation with 5 nM, 10 nM, and 25 nM MISA A, respectively. Recovery was also dose- and time-dependent. The actin-disrupting effects were not reversible when the cells were incubated with MISA A at a low dose (10 nM) for 24 hr or a high dose (25 nM) for 30 min. Topical administration of MISA A significantly decreased IOP in rats by 5.8 +/- 0.5 (mean +/- SEM) (p < 0.05) Tonopen rat units. In monkeys, IOP was decreased by 3.8 +/- 0.5 mmHg (p < 0.001) in the normotensive eye and by 9.2 +/- 1.2 mmHg (p < 0.001) in the glaucomatous eye.
MISA A greatly altered the actin cytoskeleton and cellular adhesions and reduced IOP, suggesting that MISA A may be a useful antiglaucoma strategy.
确定导致肌动蛋白丝解聚的米沙诺内酯A（MISA）对培养的人小梁网（HTM）细胞的肌动蛋白细胞骨架以及对活体大鼠和猴子眼内压（IOP）的影响。
用MISA A处理培养的HTM细胞，通过免疫荧光显微镜确定肌动蛋白细胞骨架的变化。通过对小梁网（TM）进行单侧激光光凝在食蟹猴中诱导眼压升高。在血压正常的大鼠（眼压计）和青光眼猴子（气动眼压计和眼压计）中，于0.5、1、2、3、4、5和6小时测定局部应用MISA A后的眼压反应。
MISA A在培养的HTM细胞中引起肌动蛋白应力纤维的剂量和时间依赖性破坏。分别用5 nM、10 nM和25 nM MISA A孵育2小时、30分钟和10分钟后，肌动蛋白微丝和含纽蛋白的粘着斑恶化。恢复也是剂量和时间依赖性的。当细胞用低剂量（10 nM）MISA A孵育24小时或高剂量（25 nM）孵育30分钟时，肌动蛋白破坏作用不可逆。局部应用MISA A使大鼠眼压显著降低5.8±0.5（平均值±标准误）（p<0.05）眼压计大鼠单位。在猴子中，血压正常的眼睛眼压降低3.8±0.5 mmHg（p<0.001），青光眼眼睛眼压降低9.2±1.2 mmHg（p<0.001）。
MISA A极大地改变了肌动蛋白细胞骨架和细胞粘附并降低了眼压，表明MISA A可能是一种有用的抗青光眼策略。
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