AUTHOR=Wang Yi , Wang Xiuli , Chen Selena , Tian Xiaoyu , Zhang Lulu , Huang Yaqian , Tang Chaoshu , Du Junbao , Jin Hongfang 

TITLE=Sulfur Dioxide Activates Cl-/HCO3- Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00313

DOI=10.3389/fphar.2019.00313

ISSN=1663-9812

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