Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice.
Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 microL, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3.
Tang
Jiping
J
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport 33932, USA.
Liu
Jun
J
Zhou
Changman
C
Alexander
J Steven
JS
Nanda
Anil
A
Granger
D Neil
DN
Zhang
John H
JH
D000818:Animals; D001777:Blood Coagulation; D001794:Blood Pressure; D001812:Blood-Brain Barrier; D001929:Brain Edema / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology; D002536:Cerebral Arteries / Q000166:cytology / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D017364:Collagenases; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
D007074:Immunoglobulin G; D003094:Collagen; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose