Sulfur Dioxide Activates Cl(-)/HCO(3)(-) Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells

Sulfur dioxide (SO(2)) is a colorless and irritating gas. Recent studies indicate that SO(2) acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pH(i)). Transmembrane cystein mutation of Na(+)- independent Cl(-)/HCO(3)(-) exchanger (anion exchanger, AE) affects pH(i). However, whether SO(2) inhibits VSMC proliferation by reducing pH(i) is still unknown. Here, we investigated whether SO(2) reduced pH(i) to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50–200 μM, SO(2) was found to lower the pH(i) in VSMCs. Concurrently, NH(4)Cl pre-perfusion showed that SO(2) significantly activated AE, whereas the AE inhibitor 4,4′-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO(2) on pH(i) in VSMCs. While 200 μM SO(2) sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO(2), thereby restoring the pH(i) in VSMCs. Furthermore, DIDS pretreatment eliminated SO(2)-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO(2) inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.