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 (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 Ca2+ 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. (Arterioscler Thromb Vasc Biol. 2012;32:2670-2677.)