Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

Abstract

Hypoxic-ischemic brain injury is a leading cause of neurodevelopmental morbidities in preterm and full-term infants. Blood-brain barrier dysfunction represents an important component of perinatal hypoxic-ischemic brain injury. The extracellular matrix (ECM) is a vital component of the blood-brain barrier. Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are important ECM components. They contribute to brain development, blood-brain barrier maintenance, and to regenerative and repair processes after hypoxic-ischemic brain injury. We hypothesized that ischemia at different durations of reperfusion affects the ECM protein composition of MMPs and TIMPs in the cerebral cortex of fetal sheep. Cerebral cortical samples were snap-frozen from sham control fetuses at 127 days of gestation and from fetuses after exposure to 30-min carotid occlusion and 4-, 24-, and 48-h of reperfusion. Protein expression of MMP-2, -8, -9, and -13 and TIMP-1, -2, -3, and -4 was measured by Western immunoblotting along with the gelatinolytic activity of MMP-2 and MMP-9 by zymography. The expression of MMP-8 was increased (Kruskal-Wallis, p = 0.04) in fetuses 48 h after ischemia. In contrast, changes were not observed in the protein expression of MMP-2, -9, or -13. The gelatinolytic activity of pro-MMP-2 was increased (ANOVA, p = 0.02, Tukey HSD, p = 0.05) 24 h after ischemia. TIMP-1 and -3 expression levels were also higher (TIMP-1, ANOVA, p = 0.003, Tukey HSD, p = 0.01; TIMP-3, ANOVA, p = 0.006, Tukey HSD, p = 0.01) 24 h after ischemia compared with both the sham controls and with fetuses exposed to 4 h of reperfusion. The changes in the expression of TIMP-1, -2, and -3 correlated with the changes in the MMP-8 and -13 protein expression. We speculate that regulation of MMP-8, MMP-13, and TIMPs contributes to ECM remodeling after is chemic-reperfusion injury in the fetal brain.

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…As already cited above, reperfusion after ischemia triggers a particular set of potential damaging mechanisms, and an eventful one is the activation of matrix metalloproteinases (MMP), a class that comprises, among others, gelatinases (MMP-2 and -9) and collagenases (MMP-8 and -13) [385]. MMPs are important regulators of several metabolic mechanisms such as the extracellular matrix remodeling, and also regulate immune responses [386], blood–brain barrier maintenance, and regenerative and structural repairing after IRI in the brain [385]. However, in the pathological context of I/R, MMPs may promote the degradation of intracellular proteins and lead to structural and functional impairment, as we previously stated in this review.…”

Agomelatine prevents macrophage infiltration and brain endothelial cell damage in a stroke mouse model

“…Thrombolytic therapy and mechanical recanalization are effective methods for blood re-supply after ischemia. However, for some specific patients, the injury induced by ischemia can be aggravated by ischemic/reperfusion, which is termed as “brain ischemic/reperfusion injury” [ 30 ].…”

Integrative Analysis of the Roles of lncRNAs and mRNAs in Itaconate-Mediated Protection Against Liver Ischemia-Reperfusion Injury in Mice

“… 41 Although research on MMP-13 in liver IR injury is not available, a study suggested that MMP-13 is important in IR-related brain injury, and the level of MMP-13 gradually increased with time after cerebral IR and was markedly higher than that in the sham group after 48 hours. 42 CCL3 and CCL4, also known as macrophage inflammatory protein-1α (MIP-1α) and macrophage inflammatory protein-1β (MIP-1β), were examined in liver endothelial cells several hours after liver transplantation reperfusion, and they were continuously expressed during acute cellular rejection. It seemed that inhibition of the secretion of these chemokines was one of the mechanisms of the success of corticosteroid therapy for acute rejection.…”