Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice.
To investigate the role of brain angiotensin II (ANG II) in the pathogenesis of injury following ischemic stroke, mice overexpressing renin and angiotensinogen (R+A+) and their wild-type control animals (R-A-) were used for experimental ischemia studies. Focal brain ischemia was induced by middle cerebral artery occlusion (MCAO). The severity of ischemic injury was determined by measuring neurological deficits and histological damage at 24 and 48 h after MCAO, respectively. To exclude the influence of blood pressure and local collateral blood flow, brain slices were used for oxygen and glucose deprivation (OGD) studies. The severity of OGD-induced damage was determined by measuring indicators of tissue swelling and cell death, the intensity of the intrinsic optical signal (IOS), and the number of propidium iodide (PI) staining cells, respectively. Results showed 1) R+A+ mice showed higher neurological deficit score (3.8 +/- 0.5 and 2.5 +/- 0.3 for R+A+ and R-A-, respectively, P < 0.01) and larger infarct volume (22.2 +/- 1.6% and 14.1 +/- 1.2% for R+A+ and R-A-, respectively, P < 0.01); 2) The R+A+ brain slices showed more severe tissue swelling and cell death in the cortex (IOS: 140 +/- 6% and 114 +/- 10%; PI: 139 +/- 20 cells/field and 39 +/- 9 cells/field for R+A+ and R-A-, respectively, P < 0.01); 3) treatment with losartan (20 micromol/l) abolished OGD-induced exaggeration of cell injury seen in R+A+ mice. The data indicate that activation of ANG II/AT(1) signaling is harmful to brain exposed to ischemia.
Chen
Shuzhen
S
Departments of Pharmacology and Toxicology, Wright State University, Dayton, Ohio, USA.
Li
Guangze
G
Zhang
Wenfeng
W
Wang
Jinju
J
Sigmund
Curt D
CD
Olson
James E
JE
Chen
Yanfang
Y
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D019808:Losartan