Postischemic brain injury is exacerbated in mice lacking the kinin B2 receptor.
Kallikrein cleaves low molecular weight kininogen to generate vasoactive kinins, which bind to the kinin B2 receptor, triggering a host of biological effects. Kallikrein gene delivery has been shown previously to reduce ischemia/reperfusion-induced cerebral infarction. In this study, we tested the hypothesis that the kinin B2 receptor plays a protective role in ischemic brain injury using kinin B2 receptor gene knockout (B2R-KO) mice subjected to middle cerebral artery occlusion (MCAO). The mortality rate and neurological deficit scores of B2R-KO mice (n=48) after MCAO were significantly increased compared with wild-type (WT) mice (n=40) when examined over a 14-day period. In addition, the infarct volume in B2R-KO mice was significantly larger than in WT mice at days 1 and 3 after MCAO. Similarly, apoptotic cells, detected by TUNEL labeling counterstained with propidium iodide, and caspase-3 activity in the ischemic brain increased significantly in B2R-KO mice at days 1 and 3 after MCAO. Furthermore, the accumulation of neutrophils in the ischemic brain of B2R-KO mice after MCAO increased when compared with WT mice and was associated with elevated tumor necrosis factor alpha expression. These alterations in B2R-KO mice correlated with decreased NO levels, Akt, and glycogen synthase kinase-3beta phosphorylation and increased nicotinamide-adenine dinucleotide oxidase activity. These results indicate that the kinin B2 receptor promotes survival and protects against brain injury by suppression of apoptosis and inflammation induced by ischemic stroke.
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Chun-Fang
CF
Xia
Robert S
RS
Smith
Bo
B
Shen
Zhi-Rong
ZR
Yang
Cesar V
CV
Borlongan
Lee
L
Chao
Julie
J
Chao
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology; D018696:Neuroprotective Agents / Q000378:metabolism; D020556:Neutrophil Infiltration; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000172:deficiency* / Q000378:metabolism; D020521:Stroke / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D009566:Nitrates; D009573:Nitrites; D043782:Receptor, Bradykinin B2; D014409:Tumor Necrosis Factor-alpha; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3