Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury.
Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury.
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DOI：
10.1523/jneurosci.5832-08.2009
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发表时间：
2009-02-25
期刊：
影响因子：
--
通讯作者：
Hagberg H
中科院分区：
文献类型：
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作者：
Wang X;Carlsson Y;Basso E;Zhu C;Rousset CI;Rasola A;Johansson BR;Blomgren K;Mallard C;Bernardi P;Forte MA;Hagberg H
亲环素D（CypD）是线粒体膜渗透性转换孔（PTP）的调节剂，可增强脑中Ca 2+诱导的线粒体透化和细胞死亡。然而，CypD在不同发育年龄的缺氧缺血性（HI）脑损伤中的作用尚不清楚。在出生后第9天（P）或第60天，对CypD缺陷[敲除（KO）]、野生型（WT）和杂合小鼠的同窝仔进行HI，并在HI后7天评价脑损伤。CypD缺乏导致在P60时HI脑损伤显著减少，但在P9时损伤恶化。HI后，在P9 CypD KO小鼠中诱导的caspase依赖性和非依赖性细胞死亡途径比WT对照更多，并且在P60时凋亡活化最小。PTP有一个相当高的诱导阈值和较低的敏感性环孢素A在新生小鼠与成年小鼠。与此相反，Bax的抑制显着减少半胱天冬酶激活和脑损伤的未成年小鼠，但在成年大脑无效。我们的研究结果表明，CypD/PTP是至关重要的脑损伤的发展在成年人，而在未成熟的大脑中占主导地位的依赖机制。CypD在HI中的作用从未成熟脑中的主要促存活蛋白转变为成人脑中的细胞死亡介导剂。
Cyclophilin D (CypD), a regulator of the mitochondrial membrane permeability transition pore (PTP), enhances Ca2+-induced mitochondrial permeabilization and cell death in the brain. However, the role of CypD in hypoxic-ischemic (HI) brain injury at different developmental ages is unknown. At postnatal day (P) 9 or P60, littermates of CypD-deficient [knock-out (KO)], wild-type (WT), and heterozygous mice were subjected to HI, and brain injury was evaluated 7 d after HI. CypD deficiency resulted in a significant reduction of HI brain injury at P60 but worsened injury at P9. After HI, caspase-dependent and -independent cell death pathways were more induced in P9 CypD KO mice than in WT controls, and apoptotic activation was minimal at P60. The PTP had a considerably higher induction threshold and lower sensitivity to cyclosporin A in neonatal versus adult mice. On the contrary, Bax inhibition markedly reduced caspase activation and brain injury in immature mice but was ineffective in the adult brain. Our findings suggest that CypD/PTP is critical for the development of brain injury in the adult, whereas Bax-dependent mechanisms prevail in the immature brain. The role of CypD in HI shifts from a predominantly prosurvival protein in the immature to a cell death mediator in the adult brain.