Endogenous SO(2)-dependent Smad3 redox modification controls vascular remodeling

Sulfur dioxide (SO(2)) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO(2) influences its upper-stream targets have been elusive. Here we show that SO(2) may mediate conversion of hydrogen peroxide (H(2)O(2)) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H(2)O(2) to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO(2). Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO(2), among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor β signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO(2) on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO(2) in vascular pathophysiology through a redox-dependent mechanism.