Vascular PPARδ protects against stroke-induced brain injury
Ke-Jie Yin1, Zhen Deng, Milton Hamblin
1Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. kejie@umich.edu
Objective:
To investigate the effects of peroxisome proliferator-activated receptor (PPAR)δ in the cerebral vasculature following stroke-induced brain injury.
Methods And Results:
Here, we report a novel finding that selective PPARδ genetic deletion in vascular smooth muscle cells (VSMCs) resulted in increased cerebrovascular permeability and brain infarction in mice after middle cerebral artery occlusion (MCAO). Mechanistically, we revealed for the first time that PPARδ expression is reduced, but matrix metalloproteinase (MMP)-9 activity is increased in cultured VSMCs after oxygen-glucose deprivation and also in the cerebral cortex of mice following MCAO. Moreover, gain- and loss of PPARδ function in VSMCs significantly reduces and increases oxygen-glucose deprivation-induced MMP-9 activity, respectively. We have further identified that MMP-9 is a direct target of PPARδ-mediated transrepression by chromatin immunoprecipitation and PPARδ transcriptional activity assays. Furthermore, inhibition of MMP-9 activity by lentiviral MMP-9 short hairpin RNA effectively improves cerebrovascular permeability and reduces brain infarction in VSMC-selective PPARδ conditional knockout mice after MCAO.
Conclusions:
Our data demonstrate that PPARδ in VSMCs can prevent ischemic brain injury by inhibition of MMP-9 activation and attenuation of postischemic inflammation. The pharmacological activation of PPARδ may provide a new therapeutic strategy to treat stroke-induced vascular and neuronal damage.
Insights
Peroxisome proliferator-activated receptor (PPAR)δ in vascular smooth muscle cells protects against stroke. Inhibiting matrix metalloproteinase-9 (MMP-9) activation by PPARδ reduces brain damage and inflammation after ischemic stroke.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Molecular Medicine
Background:
- Stroke-induced brain injury involves cerebrovascular damage.
- Peroxisome proliferator-activated receptor (PPAR)δ is implicated in vascular function.
- The role of PPARδ in the cerebral vasculature post-stroke is not fully understood.
Purpose of the Study:
- To investigate the role of PPARδ in vascular smooth muscle cells (VSMCs) following stroke.
- To elucidate the mechanisms by which PPARδ influences cerebrovascular integrity and brain injury.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in mice.
- Selective genetic deletion of PPARδ in VSMCs.
- Oxygen-glucose deprivation (OGD) in cultured VSMCs.
- Chromatin immunoprecipitation and transcriptional activity assays.
- Inhibition of matrix metalloproteinase-9 (MMP-9) activity.
Main Results:
- PPARδ deletion in VSMCs increased cerebrovascular permeability and brain infarction post-MCAO.
- PPARδ deficiency upregulated MMP-9 activity in VSMCs and cerebral cortex post-stroke.
- PPARδ directly transrepresses MMP-9 expression.
- Inhibiting MMP-9 improved cerebrovascular integrity and reduced infarction in PPARδ-deficient mice.
Conclusions:
- PPARδ in VSMCs mitigates ischemic brain injury by suppressing MMP-9 activation.
- PPARδ activation attenuates post-stroke inflammation and vascular damage.
- Pharmacological targeting of PPARδ presents a potential therapeutic strategy for stroke.
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