Sulfur Dioxide Activates Cl/HCO Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells.

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