Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, PSC 612, Los Angeles, CA 90033, USA.
Neurochem Res. 2011 Oct;36(10):1870-5. doi: 10.1007/s11064-011-0508-0. Epub 2011 May 27.
Although the systemic effects of progestogens have been extensively studied, little is known in regards to the cellular effects of these compounds. Using a cellular model for vascular (macrophages) and brain (microglial) cells, we studied the effects of various progestogens, either alone or in combination with 17β-estradiol (E(2)) on the activity of matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme involved in vascular remodeling and plaque destabilization in cardiovascular events, blood-brain barrier breakdown in stroke and brain regeneration and neurovascular remodeling during repair phases of brain injury. In the absence of E(2), medroxyprogesterone acetate (MPA), a synthetic progestogen and progesterone (PG) metabolites tended to increase MMP-9 enzyme activity in macrophages and microglial cells, whereas PG decreased such activity in macrophages; exceptions being that MPA and the PG metabolite, pregnanediol (Pdiol) had no effect on macrophage MMP-9 enzyme activity and PG had no effect on microglial cell MMP-9 enzyme activity. In the presence of E(2), an opposite affect was observed whereby MPA and the PG metabolites tended to decrease MMP-9 enzyme activity from macrophages and microglial cells, whereas PG had no effect; exceptions being that MPA and Pdiol had no effect on macrophage MMP-9 enzyme activity. In conclusion, these results demonstrate that the effects of PG, PG metabolites and MPA on MMP-9 enzyme activity differ across vascular and brain cells when administered alone or in combination with E(2) which could have important mechanistic implications for hormone therapy.
尽管孕激素的全身作用已得到广泛研究，但对于这些化合物的细胞作用知之甚少。本研究使用血管（巨噬细胞）和脑（小胶质细胞）的细胞模型，研究了各种孕激素（单独或与 17β-雌二醇（E2）联合使用）对基质金属蛋白酶-9（MMP-9）活性的影响，MMP-9 是一种参与心血管事件中血管重塑和斑块不稳定、中风时血脑屏障破坏以及脑损伤修复阶段中脑再生和神经血管重塑的蛋白水解酶。在没有 E2 的情况下，醋酸甲羟孕酮（MPA）是一种合成孕激素和孕激素（PG）代谢物，往往会增加巨噬细胞和小胶质细胞中 MMP-9 酶的活性，而 PG 则会降低巨噬细胞中的这种活性；MPA 和 PG 代谢物孕烷二醇（Pdiol）对巨噬细胞 MMP-9 酶活性没有影响，PG 对小胶质细胞 MMP-9 酶活性没有影响是例外。在存在 E2 的情况下，观察到相反的影响，即 MPA 和 PG 代谢物往往会降低巨噬细胞和小胶质细胞中 MMP-9 酶的活性，而 PG 则没有影响；MPA 和 Pdiol 对巨噬细胞 MMP-9 酶活性没有影响是例外。总之，这些结果表明，PG、PG 代谢物和 MPA 对 MMP-9 酶活性的影响在单独或与 E2 联合使用时在血管和脑细胞中不同，这可能对激素治疗具有重要的机制意义。
