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Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2004 Feb; Vol. 43 (2), pp. 452-9. Date of Electronic Publication: 2003 Dec 29. - Publication Year :
- 2004
-
Abstract
- Kallikrein/kinin has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of kallikrein gene transfer in cerebral ischemia. Adult, male Sprague-Dawley rats were subjected to a 1-hour occlusion of the middle cerebral artery followed by intracerebroventricular injection of adenovirus harboring either the human tissue kallikrein gene or the luciferase gene. Kallikrein gene transfer significantly reduced ischemia-induced locomotor deficit scores and cerebral infarction after cerebral ischemia injury. Expression of recombinant human tissue kallikrein was identified and localized in monocytes/macrophages of rat ischemic brain by double immunostaining. Morphological analyses showed that kallikrein gene transfer enhanced the survival and migration of glial cells into the ischemic penumbra and core, as identified by immunostaining with glial fibrillary acidic protein. Cerebral ischemia markedly increased apoptotic cells, and kallikrein gene delivery reduced apoptosis to near-normal levels as seen in sham control rats. In primary cultured glial cells, kinin stimulated cell migration but inhibited hypoxia/reoxygenation-induced apoptosis in a dose-dependent manner. The effects of kinin on both migration and apoptosis were abolished by icatibant, a bradykinin B2 receptor antagonist. Enhanced cell survival after kallikrein gene transfer occurred in conjunction with markedly increased cerebral nitric oxide levels and phospho-Akt and Bcl-2 levels but reduced caspase-3 activation, NAD(P)H oxidase activity, and superoxide production. These results indicate that kallikrein gene transfer provides neuroprotection against cerebral ischemia injury by enhancing glial cell survival and migration and inhibiting apoptosis through suppression of oxidative stress and activation of the Akt-Bcl-2 signaling pathway.
- Subjects :
- Adenoviridae genetics
Animals
Brain metabolism
Brain pathology
Brain Ischemia diagnosis
Brain Ischemia metabolism
Caspases metabolism
Cell Movement
Cell Survival
Cells, Cultured
Cerebral Cortex pathology
Cerebral Infarction pathology
Cerebral Infarction prevention & control
Genetic Vectors
Male
NADPH Oxidases metabolism
Neuroglia cytology
Nitric Oxide metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
Stroke diagnosis
Stroke pathology
Superoxides metabolism
Tissue Kallikreins analysis
Tissue Kallikreins metabolism
Apoptosis
Brain Ischemia prevention & control
Kallikreins genetics
Neuroglia physiology
Neuroprotective Agents
Stroke prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 43
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 14698996
- Full Text :
- https://doi.org/10.1161/01.HYP.0000110905.29389.e5