Extracellular Acidification Activates cAMP Responsive Element Binding Protein via Na+/H+ Exchanger Isoform 1–Mediated Ca2+ Oscillation in Central Nervous System Pericytes
Objective—We have previously shown that Na+/H+ exchanger isoform 1 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 Na+/H+ exchanger isoform 1–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 Ca2+ oscillation and subsequently phosphorylated Ca2+/calmodulin-dependent kinase II 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 Na+/H+ exchanger isoform 1, leading to Ca2+/calmodulin-dependent kinase II–dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the Na+/H+ exchanger isoform 1-Ca2+/calmodulin-dependent kinase II–CREB pathway in brain pericytes and may thus modulate brain ischemic insult.
- Received June 8, 2011.
- Accepted July 31, 2012.
- © 2012 American Heart Association, Inc.