Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury.
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 delta (PPARdelta) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARdelta is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARdelta 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 PPARdelta 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 PPARdelta. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARdelta 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 PPARdelta 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 PPARdelta-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction.
Yin
Ke-Jie
KJ
Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Deng
Zhen
Z
Hamblin
Milton
M
Xiang
Yi
Y
Huang
Huarong
H
Zhang
Jifeng
J
Jiang
Xiaodan
X
Wang
Yanzhuang
Y
Chen
Y Eugene
YE
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000517:prevention & control*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
C425931:GW 501516; D035683:MicroRNAs; C544301:Mirn15a microRNA, mouse; D047494:PPAR delta; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; C505409:Casp3 protein, mouse; D053148:Caspase 3
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