Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia

Abstract

Matrix metalloproteinase-9 (MMP-9) plays a benefi cial role in the sub-acute phase after ischemic stroke. However, unrestrained MMP-9 may disrupt the blood-brain barrier (BBB), which has limited its use for the treatment of brain ischemia. In the present study, we constructed lentivirus mediated hypoxiacontrolled MMP-9 expression and explored its role after stroke. Hypoxia response element (HRE) was used to confine MMP-9 expression only to the hypoxic region of mouse brain after 120-min transient middle cerebral artery occlusion. Lentiviruses were injected into the peri-infarct area on day 7 after transient ischemia. We found hyperexpression of exogenous HRE-MMP-9 under the control of hypoxia, and its expression was mainly located in neurons and astrocytes without aggravation of BBB damage compared to the CMV group. Furthermore, mice in the HRE-MMP-9 group showed the best behavioral recovery compared with the normal saline, GFP, and SB-3CT groups. Therefore, hypoxia-controlled MMP-9 hyperexpression during the sub-acute phase of ischemia may provide a novel promising approach of gene therapy for stroke.

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

“…This vector made it possible to use MMP-9 to treat brain ischemia. 9 Our results showed that the brain atrophy volume was reduced and neurological function was improved when injecting HRE-MMP-9 into the peri-infarct area 7 days after tMCAO. On the basis of previous studies, MMP-9 had detrimental effects, including BBB disruption, inflammation, and neurotoxicity in the acute phase of stroke (the first 3 days), but it could help to mediate repair in the late stage of ischemia (7-14 days).…”

“…7,8 Our previous study showed that the hypoxiainducible factor (HIF)-1a-hypoxia response element (HRE) system could successfully control MMP-9 expression, and HRE-MMP-9 overexpression in the ischemic mouse brain promoted behavioral recovery. 9 However, the therapeutic mechanism is still unclear.…”

“…We previously identified that HRE-MMP-9 expression did not aggravate the blood-brain barrier (BBB) permeability in the post-ischemic brain. 9 In this study, we aimed to investigate the effect of MMP-9 overexpression on glial scar degradation and angiogenesis, which contribute to subsequent neurogenesis, and we further explored the molecular mechanisms involved in neurovascular remodeling in delayed stroke after HRE-MMP-9 treatment.…”

Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity

“…SB-3CT blocks MMP9 activity through an irreversible covalent interaction (Jia et al, 2014; Sassoli et al, 2014). Mice were treated with 10 mg/kg SB-3CT daily starting 24 hours prior to injury in combination with MMP9-specific collagen matrix injections (Cai et al, 2015). Auf1 KO mice treated with SB-3CT showed near complete extinction of MMP9 activity at the site of IP injection and significantly reduced MMP9 activity in the injured TA muscle (Figure 6A).…”

Triptolide Protects Neurons from Endoplasmic Reticulum Stress-Mediated Apoptosis in Cerebral Ischemic Injury Rats

“…Ischemic stroke is one of the main causes of mortality and disability worldwide [1]. During ischemic stroke, the blockage of cerebral blood flow leads to brain damage and neuronal death through a series of pathological mechanisms including endoplasmic reticulum (ER) stress.…”