PDF(Pubmed)
Abstract：
Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.
摘要：
缺血性中风后再灌注（IR）导致广泛的脑血管损伤，其特征是神经炎症和脑细胞死亡。抑制基质金属蛋白酶-3（MMP-3）是减轻IR引起的中风损伤的有希望的治疗方法。我们采用大脑中动脉闭塞和随后的再灌注（MCAO/R）来模拟成年小鼠的缺血性中风。具体来说,我们使用MCAO后48h收集的卒中脑的RNA测序(RNA-seq)研究了MMP-3敲除(KO)对卒中病理生理学的影响.MMP-3KO显著减少卒中后脑梗塞面积。值得注意的是,RNA-seq分析表明，MMP-3KO改变了男性中风大脑中333个基因（252个下调）的表达，改变了女性中风大脑中3768个基因（889个下调）的表达。功能通路分析显示，炎症，整合素细胞表面信号，内皮-和上皮-间质转化（EndMT/EMT），MMP-3KO卒中脑中的凋亡基因特征降低。有趣的是，MMP-3KO下调女性的基因特征比男性更深刻，如更大的负富集分数所示。我们的研究强调MMP-3抑制是一种有前途的治疗策略，影响中风后的多种细胞通路。
