Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice.
Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice but not in tissue plasminogen activator (tPA)-deficient knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans.
Zhao
Bing-Qiao
BQ
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Ikeda
Yasuhiko
Y
Ihara
Hayato
H
Urano
Tetsumei
T
Fan
WenYing
W
Mikawa
Sumiko
S
Suzuki
Yasuhiro
Y
Kondo
Kazunao
K
Sato
Kohji
K
Nagai
Nobuo
N
Umemura
Kazuo
K
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced* / Q000150:complications; D001483:Base Sequence; D002545:Brain Ischemia / Q000139:chemically induced* / Q000150:complications; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D017931:DNA Primers; D004195:Disease Models, Animal; D004790:Enzyme Induction; D006493:Heparin / Q000494:pharmacology*; D017403:In Situ Hybridization; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D020768:Middle Cerebral Artery; D016133:Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D006493:Heparin; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9