Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca 2+ oscillation in central nervous system pericytes

Kuniyuki Nakamura, Masahiro Kamouchi, Koichi Arimura, ataru nishimura, Junya Kuroda, Koji Ishitsuka, Himiko Tokami, Hiroshi Sugimori, Tetsuro Ago, Takanari Kitazono

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Abstract

Objective-We have previously shown that Na+/H+ exchanger isoform 1 (NHE1) plays an important role in Ca2+ signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca2+ signaling during acidosis is transformed into cellular responses in CNS pericytes. Methods and Results-Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na+ or low pH generated Ca 2+ oscillation and subsequently phosphorylated Ca2+/ calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. Conclusion-Our results indicate that extracellular acidosis induces Ca2+ oscillation via NHE1, leading to Ca2+/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.

Original languageEnglish
Pages (from-to)2670-2677
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number11
DOIs
Publication statusPublished - Nov 1 2012

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Pericytes
Sodium-Hydrogen Antiporter
Carrier Proteins
Protein Isoforms
Central Nervous System
Calcium-Calmodulin-Dependent Protein Kinases
Acidosis
Interleukin-6
Middle Cerebral Artery Infarction
Brain
Brain Ischemia
Luciferases
Fluorescent Antibody Technique
Up-Regulation
Western Blotting
Phosphorylation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca 2+ oscillation in central nervous system pericytes",
abstract = "Objective-We have previously shown that Na+/H+ exchanger isoform 1 (NHE1) plays an important role in Ca2+ signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca2+ signaling during acidosis is transformed into cellular responses in CNS pericytes. Methods and Results-Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na+ or low pH generated Ca 2+ oscillation and subsequently phosphorylated Ca2+/ calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. Conclusion-Our results indicate that extracellular acidosis induces Ca2+ oscillation via NHE1, leading to Ca2+/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.",
author = "Kuniyuki Nakamura and Masahiro Kamouchi and Koichi Arimura and ataru nishimura and Junya Kuroda and Koji Ishitsuka and Himiko Tokami and Hiroshi Sugimori and Tetsuro Ago and Takanari Kitazono",
year = "2012",
month = "11",
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doi = "10.1161/ATVBAHA.112.254946",
language = "English",
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pages = "2670--2677",
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number = "11",

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T1 - Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca 2+ oscillation in central nervous system pericytes

AU - Nakamura, Kuniyuki

AU - Kamouchi, Masahiro

AU - Arimura, Koichi

AU - nishimura, ataru

AU - Kuroda, Junya

AU - Ishitsuka, Koji

AU - Tokami, Himiko

AU - Sugimori, Hiroshi

AU - Ago, Tetsuro

AU - Kitazono, Takanari

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Objective-We have previously shown that Na+/H+ exchanger isoform 1 (NHE1) plays an important role in Ca2+ signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca2+ signaling during acidosis is transformed into cellular responses in CNS pericytes. Methods and Results-Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na+ or low pH generated Ca 2+ oscillation and subsequently phosphorylated Ca2+/ calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. Conclusion-Our results indicate that extracellular acidosis induces Ca2+ oscillation via NHE1, leading to Ca2+/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.

AB - Objective-We have previously shown that Na+/H+ exchanger isoform 1 (NHE1) plays an important role in Ca2+ signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca2+ signaling during acidosis is transformed into cellular responses in CNS pericytes. Methods and Results-Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na+ or low pH generated Ca 2+ oscillation and subsequently phosphorylated Ca2+/ calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. Conclusion-Our results indicate that extracellular acidosis induces Ca2+ oscillation via NHE1, leading to Ca2+/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.

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