Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA.
Health Sciences Center, Tulane University, New Orleans, LA 70112, USA.
Int J Mol Sci. 2024 Jul 5;25(13):7383. doi: 10.3390/ijms25137383.
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.
缺血性中风后继发再灌注（IR）会导致广泛的脑血管损伤，其特征为神经炎症和脑细胞死亡。基质金属蛋白酶-3（MMP-3）的抑制作用作为一种有前途的治疗方法，可以减轻 IR 引起的中风损伤。我们采用大脑中动脉闭塞后继发再灌注（MCAO/R）的方法在成年小鼠中建立缺血性中风模型。具体而言，我们通过对 MCAO 后 48 小时采集的中风大脑进行 RNA 测序（RNA-seq），研究了 MMP-3 敲除（KO）对中风病理生理学的影响。MMP-3 KO 显著减少了中风后的脑梗死面积。值得注意的是，RNA-seq 分析显示，MMP-3 KO 改变了雄性中风大脑中 333 个基因（252 个下调）和雌性中风大脑中 3768 个基因（889 个下调）的表达。功能途径分析表明，炎症、整合素细胞表面信号、内皮-上皮转化（EndMT/EMT）和细胞凋亡基因特征在 MMP-3 KO 中风大脑中减少。有趣的是，MMP-3 KO 在雌性中下调的基因特征比在雄性中更为显著，表现为更大的负富集评分。我们的研究强调了 MMP-3 抑制作为一种有前途的治疗策略，可以影响中风后的多个细胞途径。
