Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury

Background: An increase in intracellular calcium concentration [Ca2+](i) is one of the first events to take place after brain ischemia. A key [Ca2+](i)-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we h...

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Bibliographic Details
Authors: Sobrado, Monica, Ramirez, Belen G., Neria, Fernando, Lizasoain, Ignacio, Arbones, Marie Lourdes, Minami, Takashi, Redondo, Juan Miguel, Moro, Maria Angeles, Cano, Eva
Format: article
Publication Date:2012
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/6523
Online Access:http://hdl.handle.net/20.500.12105/6523
Access Level:Open access
Keyword:Calcineurin
Calcium
Glia
Hypoxia
Inflammation
Rcan1
Stroke
SYNDROME CRITICAL REGION-1
DOWN-SYNDROME
CEREBRAL-ISCHEMIA
T-CELLS
PHOSPHATASE CALCINEURIN
OXIDATIVE STRESS
GENE-EXPRESSION
UP-REGULATION
NEURAL CELLS
ASTROCYTES
Description
Summary:Background: An increase in intracellular calcium concentration [Ca2+](i) is one of the first events to take place after brain ischemia. A key [Ca2+](i)-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we have analyzed the role of endogenous regulator of CN 1 (Rcan1) in response to experimental ischemic stroke induced by middle cerebral artery occlusion. Methods: Animals were subjected to focal cerebral ischemia with reperfusion. To assess the role of Rcan1 after stroke, we measured infarct volume after 48 h of reperfusion in Rcan1 knockout (KO) and wild-type (WT) mice. In vitro studies were performed in astrocyte-enriched cortical primary cultures subjected to 3\% oxygen (hypoxia) and glucose deprivation (HGD). Adenoviral vectors were used to analyze the effect of overexpression of Rcan1-4 protein. Protein expression was examined by immunohistochemistry and immunoblotting and expression of mRNA by quantitative real-time Reverse-Transcription Polymerase Chain Reaction (real time qRT-PCR). Results: Brain ischemia/reperfusion (I/R) injury in vivo increased mRNA and protein expression of the calcium-inducible Rcan1 isoform (Rcan1-4). I/R-inducible expression of Rcan1 protein occurred mainly in astroglial cells, and in an in vitro model of ischemia, HGD treatment of primary murine astrocyte cultures induced Rcan1-4 mRNA and protein expression. Exogenous Rcan1-4 overexpression inhibited production of the inflammatory marker cyclo-oxygenase 2. Mice lacking Rcan1 had higher expression of inflammation associated genes, resulting in larger infarct volumes. Conclusions: Our results support a protective role for Rcan1 during the inflammatory response to stroke, and underline the importance of the glial compartment in the inflammatory reaction that takes place after ischemia. Improved understanding of non-neuronal mechanisms in ischemic injury promises novel approaches to the treatment of acute ischemic stroke.

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