Mindin is a critical mediator of ischemic brain injury in an experimental stroke model.
BACKGROUND
Stroke is the second leading cause of death among adults worldwide. Mindin is an ECM protein that plays important roles in regulating inflammation, angiogenesis and neuronal outgrowth. The role of mindin in the context of brain ischemia has not been examined.


RESULTS
Transient occlusion of the middle cerebral artery was performed on mindin knockout (KO) mice, mice that carried a neuron-specific constitutively active mindin transgene (TG) and the appropriate controls. The outcome of the ischemia was evaluated by examination of the infarct and edema volumes and by neurological score assessments. The brains were collected 24 h or 3 days following the induced stroke. Compared with the control mice, the mindin KO mice exhibited lower infarct volumes and better outcomes in the neurological tests. Mindin-deficient mice exhibited low expression levels of stroke-induced inflammatory mediators, an attenuated recruitment of inflammatory cells, and inhibited activation of NF-κB. The neuronal apoptosis levels were also lower in the brains of the mindin KO mice than in those of the control mice. The mice that expressed a neuron-specific, constitutively active mindin transgene exhibited effects following the cerebral ischemic injury that were the opposite of those that were observed in the mindin KO mice. Moreover, Akt signaling activation was elevated in the ischemic brains of mindin KO mice.


CONCLUSIONS
Mindin KO mice exhibited minor infarctions, an attenuated inflammatory response and low levels of neuronal apoptosis following an ischemic insult. These data demonstrate that mindin is a critical mediator of ischemic brain injury in an experimental stroke model. Akt signaling most likely mediates the biological function of mindin in this model of cerebral ischemia.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Lang
L
Wang
Yanyun
Y
Lu
Xin
X
Zhang
Yan
Y
Zhang
Dingsheng
D
Jiang
Xiaomin
X
Dong
Shan
S
Deng
Li
L
Yang
Yu
Y
Guan
Lihua
L
Zhu
Yan
Y
Zhou
Xiaodong
X
Zhang
Hongliang
H
Li
D000818:Animals; D020520:Brain Infarction / Q000209:etiology; D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D010982:Platelet-Derived Growth Factor; C485184:enhanced green fluorescent protein; C121491:mindin; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D051546:Cyclooxygenase 2; D051058:Oncogene Protein v-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
2,3,5-triphenyl-2H-tetrazolium chloride; Akt; Apoptosis; CBF; ECM; GSK3; ICAM-1; IL; Inflammation; Interleukin; Ischemia; MCA; MCP-1; MMP; Mindin; NF-κB; OCT; PBS; PCR; PDGF; Stroke; TLRs; TNF; TSRs; TTC; VCAM-1; cerebral blood flow; eNOS; endothelial nitric oxide synthase; extracellular matrix; glycogen synthase kinase 3; intercellular adhesion molecule-1; mTOR; mammalian target of rapamycin; matrix metalloproteinase; middle cerebral artery; monocyte chemoattractant protein-1; nuclear factor kappa B; ornithine carbamyl transferase; phosphate buffer solution; platelet-derived growth factor; polymerase chain reaction; protein kinase B; tMCAO; tPA; thrombospondin type 1 repeats; tissue plasminogen activator; toll-like receptors; transient middle cerebral artery occlusion; tumor necrosis factor; vascular cell adhesion molecule-1