Neuroprotective role of angiotensin II type 2 receptor after transient focal ischemia in mice brain.
This study assessed the time course of angiotensin (Ang) II type 1 and type 2 receptor expression after 60 min of ischemia/reperfusion in mice treated with a nonhypotensive dose of valsartan, an angiotensin II type 1 receptor antagonist. We also examined the potential neuroprotective mechanisms mediated by angiotensin II type 2 receptor. Mice were divided into two groups (n=64, each): valsartan-treated and control, vehicle groups. Infarct volume and neurological deficit scores were evaluated at several time points after ischemia, while immunohistochemical analyses were performed at serial time points after reperfusion. Valsartan significantly reduced the infarct volume and improved the neurological deficit scores (P<0.05). Both angiotensin II type 1 and type 2 receptors were upregulated at 24h and peaked at 72 h with type I receptors dominating in the ischemic penumbra of the vehicle group. Interestingly, angiotensin II type 2 receptor expression levels were significantly higher in the valsartan group than vehicle controls (P<0.001). Moreover, angiotensin II type 2 receptor upregulated phosphosignal transducer and activator of transcription-3, and B-cell lymphoma protein-2 (P<0.05). Our results indicated that angiotensin II type 2 receptor has antiapoptotic activity by activating the B-cell lymphoma protein-2 via the janus kinase/signal transducer and activator of transcription signaling pathway.
Miyamoto
Nobukazu
N
Department of Neurology, Juntendo University School of Medicine 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Zhang
Ning
N
Tanaka
Ryota
R
Liu
Meizi
M
Hattori
Nobutaka
N
Urabe
Takao
T
D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000517:prevention & control*; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015424:Reperfusion / Q000379:methods; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000627:therapeutic use*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
D057912:Angiotensin II Type 2 Receptor Blockers; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine