PT  - JOURNAL ARTICLE
AU  - Ke-Jie Yin
AU  - Zhen Deng
AU  - Milton Hamblin
AU  - Yi Xiang
AU  - Huarong Huang
AU  - Jifeng Zhang
AU  - Xiaodan Jiang
AU  - Yanzhuang Wang
AU  - Y. Eugene Chen
TI  - Peroxisome Proliferator-Activated Receptor δ Regulation of miR-15a in Ischemia-Induced Cerebral Vascular Endothelial Injury
AID  - 10.1523/JNEUROSCI.0780-10.2010
DP  - 2010 May 05
TA  - The Journal of Neuroscience
PG  - 6398--6408
VI  - 30
IP  - 18
4099  - http://www.jneurosci.org/content/30/18/6398.short
4100  - http://www.jneurosci.org/content/30/18/6398.full
SO  - J. Neurosci.2010 May 05; 30
AB  - Cerebral vascular endothelial cell (CEC) degeneration significantly contributes to blood–brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor δ (PPARδ) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARδ is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARδ overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels. To explore the molecular mechanisms, we have identified that upregulation of PPARδ can alleviate ODG-activated microRNA-15a (miR-15a) expression in CECs. Moreover, we have demonstrated that bcl-2 is a translationally repressed target of miR-15a. Intriguingly, gain- or loss-of-miR-15a function can significantly reduce or increase OGD-induced CEC death, respectively. Furthermore, we have identified that miR-15a is a transcriptional target of PPARδ. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARδ agonist, GW 501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid), significantly reduced ischemia-induced miR-15a expression, increased bcl-2 protein levels, and attenuated caspase-3 activity and subsequent DNA fragmentation in isolated cerebral microvessels, leading to decreased BBB disruption and reduced cerebral infarction in mice after transient focal cerebral ischemia. Together, these results suggest that PPARδ plays a vascular-protective role in ischemia-like insults via transcriptional repression of miR-15a, resulting in subsequent release of its posttranscriptional inhibition of bcl-2. Thus, regulation of PPARδ-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction.