Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway
Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway
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DOI：
10.1111/j.1471-4159.2006.04061.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Politi, Luis E.
中科院分区：
文献类型：
--
作者：
German, Olga Lorena;Insua, Maria Fernanda;Politi, Luis E.
识别视网膜光感受器的营养因子和激活以促进细胞存活的细胞内途径对于治疗视网膜神经退行性疾病至关重要。二十二碳六烯酸（DHA），主要的视网膜多不饱和脂肪酸，防止感光细胞凋亡在早期发育过程中在体外，并在氧化应激。然而，DHA激活的信号传导机制仍不清楚。我们研究了细胞外信号调节激酶（ERK）/丝裂原活化蛋白激酶（MAPK）或磷脂酰肌醇-3-激酶（PI 3 K）通路是否参与DHA保护。特异性MEK抑制剂1，4-二氨基-2，3-二氰基-1，4-二（2-氨基苯基）丁二烯（U 0126）可完全阻断DHA的抗凋亡作用。DHA迅速增加光感受器中ERK的磷酸化，而U 0126阻断了这种增加。U 0126阻碍DHA预防线粒体去极化，并阻断DHA诱导的视蛋白表达增加。相反，PI 3 K抑制剂并没有削弱DHA的保护作用。DHA促进光感受器中Bcl-2的早期表达，降低Bax的表达，降低caspase-3的活化。这些结果表明，DHA专门激活ERK/MAPK途径，以促进感光细胞存活在体外早期发育和氧化应激。这导致Bcl-2和Bax表达的调节，从而保持线粒体膜电位并抑制caspase活化。因此，DHA，一种脂质营养因子，通过激活由肽营养因子触发的相同信号通路来促进感光细胞存活和分化。
Identifying the trophic factors for retina photoreceptors and the intracellular pathways activated to promote cell survival is crucial for treating retina neurodegenerative diseases. Docosahexaenoic acid (DHA), the major retinal polyunsaturated fatty acid, prevents photoreceptor apoptosis during early development in vitro, and upon oxidative stress. However, the signaling mechanisms activated by DHA are still unclear. We investigated whether the extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) or the phosphatidylinositol-3-kinase (PI3K) pathway participated in DHA protection. 1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophynyltio) butadiene (U0126), a specific MEK inhibitor, completely blocked the DHA anti-apoptotic effect. DHA rapidly increased ERK phosphorylation in photoreceptors, whereas U0126 blocked this increase. U0126 hindered DHA prevention of mitochondrial depolarization, and blocked the DHA-induced increase in opsin expression. On the contrary, PI3K inhibitors did not diminish the DHA protective effect. DHA promoted the early expression of Bcl-2, decreased Bax expression and reduced caspase-3 activation in photoreceptors. These results suggest that DHA exclusively activates the ERK/MAPK pathway to promote photoreceptor survival during early development in vitro and upon oxidative stress. This leads to the regulation of Bcl-2 and Bax expression, thus preserving mitochondrial membrane potential and inhibiting caspase activation. Hence, DHA, a lipid trophic factor, promotes photoreceptor survival and differentiation by activating the same signaling pathways triggered by peptidic trophic factors.