Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling

Abstract

Sulfur dioxide (SO₂) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO₂ influences its upper-stream targets have been elusive. Here we show that SO₂ may mediate conversion of hydrogen peroxide (H₂O₂) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H₂O₂ 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 SO₂. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO₂, 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 SO₂ on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO₂ in vascular pathophysiology through a redox-dependent mechanism.