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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 ? 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.

SUBMITTER: Huang Y

PROVIDER: S-EPMC7933484 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling.

Huang Yaqian Y Li Zongmin Z Zhang Lulu L Tang Huan H Zhang Heng H Wang Chu C Chen Selena Ying SY Bu Dingfang D Zhang Zaifeng Z Zhu Zhigang Z Yuan Piaoliu P Li Kun K Yu Xiaoqi X Kong Wei W Tang Chaoshu C Jung Youngeun Y Ferreira Renan B RB Carroll Kate S KS Du Junbao J Yang Jing J Jin Hongfang H

Redox biology 20210218

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 gr ...[more]

PMID: 33647858

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Project description:Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine ?-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.

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Endogenous SO₂-dependent Smad3 redox modification controls vascular remodeling.

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Endogenous SO<sub>2</sub>-dependent Smad3 redox modification controls vascular remodeling.

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