Abstract
Sulfur dioxide (SO2) is a colorless and irritating gas. Recent studies indicate that SO2 acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pHi). Transmembrane cystein mutation of Na+- independent Cl-/HCO3- exchanger (anion exchanger, AE) affects pHi. However, whether SO2 inhibits VSMC proliferation by reducing pHi is still unknown. Here, we investigated whether SO2 reduced pHi to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50–200 μM, SO2 was found to lower the pHi in VSMCs. Concurrently, NH4Cl pre-perfusion showed that SO2 significantly activated AE, whereas the AE inhibitor 4,4′-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO2 on pHi in VSMCs. While 200 μM SO2 sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO2, thereby restoring the pHi in VSMCs. Furthermore, DIDS pretreatment eliminated SO2-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO2 inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.
Highlights
Aberrant proliferation of vascular smooth muscle cells (VSMCs) contributes to the pathological change of vascular diseases such as hypertension, diabetic angiopathy and atherosclerosis (Owens et al, 2004; Chistiakov et al, 2015; Bennett et al, 2016)
By real-time monitoring of the pHi with the fluorescent probe, we found that the SO2 donor at the concentrations of 50, 100, and 200 μM decreased the pHi in VSMCs by 0.120 ± 0.012, 0.134 ± 0.011, and 0.200 ± 0.020, respectively
Anion exchanger is the main acid loader of VSMCs, which pumps out one HCO3− in exchange for one Cl− into the cells, maintaining intracellular Cl− concentration and lowering the pHi
Summary
Aberrant proliferation of vascular smooth muscle cells (VSMCs) contributes to the pathological change of vascular diseases such as hypertension, diabetic angiopathy and atherosclerosis (Owens et al, 2004; Chistiakov et al, 2015; Bennett et al, 2016). To maintain pHi homeostasis, cells utilize ionophores on the membrane to regulate the pHi within a narrow physiological range (Cardone et al, 2005; Boron et al, 2009; Casey et al, 2010). Those ionophores include channels, pumps, exchangers and cotransporters, all of which synergistically regulate the influx and outflux of H+/HCO3− ions (Concepcion et al, 2013; Chen et al, 2018). Transforming growth factor beta 1 promotes fibroblast cell membrane AE2 expression and HCO3− excretion, which can neutralize tumor microenvironment H+ ions to inhibit tumor cell invasion (Hulikova et al, 2016). Concepcion et al (2014) found that compared with wild-type mice, the pHi of CD8+ T cells derived from AE2 knockout mice is significantly increased, and CD8+ T cell proliferation and activation levels are obviously enhanced after CD3 stimulation
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