Protein S-sulfhydration by hydrogen sulfide in cardiovascular system

Abstract

Hydrogen sulfide (H₂ S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed mechanism of H₂ S was not clear. Recently, a novel post-translational modification induced by H₂ S, named S-sulfhydration, has been proposed. S-sulfhydration is the chemical modification of specific cysteine residues of target proteins by H₂ S. There are several methods for detecting S-sulfhydration, such as the modified biotin switch assay, maleimide assay with fluorescent thiol modifying regents, tag-switch method and mass spectrometry. H₂ S induces S-sulfhydration on enzymes or receptors (such as p66Shc, phospholamban, protein tyrosine phosphatase 1B, mitogen-activated extracellular signal-regulated kinase 1 and ATP synthase subunit α), transcription factors (such as specific protein-1, kelch-like ECH-associating protein 1, NF-κB and interferon regulatory factor-1), and ion channels (such as voltage-activated Ca²⁺ channels, transient receptor potential channels and ATP-sensitive K⁺ channels) in the cardiovascular system. Although significant progress has been achieved in delineating the role of protein S-sulfhydration by H₂ S in the cardiovascular system, more proteins with detailed cysteine sites of S-sulfhydration as well as physiological function need to be investigated in further studies. This review mainly summarizes the role and possible mechanism of S-sulfhydration in the cardiovascular system. The S-sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H₂ S-related drugs in the future.

Linked articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Figure 1

Reaction mechanisms for S‐sulfhydration formation. S‐sulfhydration can be induced by H₂S on cysteine sulfenic acids (Cys‐SOH, A) or cysteine disulfides (−S‐S, B), or by polysulfides on cysteine thiols (Cys‐SH, C). H₂S induces S‐sulfhydration on cysteine thiols in oxidation conditions (D‐E).

Figure 2

Schematic illustration of possible roles of S‐sulfhydration by H₂S in the cardiovascular system. H₂S induces S‐sulfhydration on p66Shc to inhibit oxidative stress. S‐sulfhydration on phospholamban (PLN) promotes myocardial relaxation. S‐sulfhydration on protein tyrosine phosphatase 1B (PTP1B) restores endoplasmic reticulum stress homeostatis. H₂S also S‐sulfhydrates MEK1 to repair DNA damage. ATP5A1 and transient receptor potential V4 (TRPV4) S‐sulfhydration improves ATP production and vasodilatation respectively. H₂S also S‐sulfhydrates SP‐1, Keap1, NF‐κB and IRF‐1 to regulate target gene transcription, which is vital for the regulation of endothelial phenotypes, myocardial hypertrophy, oxidative stress, mitochondrial biogenesis, apoptosis and inflammation.