Vascular smooth muscle cell-derived hydrogen sulfide promotes atherosclerotic plaque stability via TFEB (transcription factor EB)-mediated autophagy

Autophagy. 2022 Oct;18(10):2270-2287. doi: 10.1080/15548627.2022.2026097. Epub 2022 Jan 28.


Vascular smooth muscle cells (VSMCs) contribute to plaque stability. VSMCs are also a major source of CTH (cystathionine gamma-lyase)-hydrogen sulfide (H2S), a protective gasotransmitter in atherosclerosis. However, the role of VSMC endogenous CTH-H2S in pathogenesis of plaque stability and the mechanism are unknown. In human carotid plaques, CTH expression in ACTA2+ cells was dramatically downregulated in lesion areas in comparison to non-lesion areas. Intraplaque CTH expression was positively correlated with collagen content, whereas there was a negative correlation with CD68+ and necrotic core area, resulting in a rigorous correlation with vulnerability index (r = -0.9033). Deletion of Cth in VSMCs exacerbated plaque vulnerability, and were associated with VSMC autophagy decline, all of which were rescued by H2S donor. In ox-LDL treated VSMCs, cth deletion reduced collagen and heightened apoptosis association with autophagy reduction, and vice versa. For the mechanism, CTH-H2S mediated VSMC autophagosome formation, autolysosome formation and lysosome function, in part by activation of TFEB, a master regulator for autophagy. Interference with TFEB blocked CTH-H2S effects on VSMCs collagen and apoptosis. Next, we demonstrated that CTH-H2S sulfhydrated TFEB at Cys212 site, facilitating its nuclear translocation, and then promoting transcription of its target genes such as ATG9A, LAPTM5 or LDLRAP1. Conclusively, CTH-H2S increases VSMC autophagy by sulfhydration and activation of TFEB, promotes collagen secretion and inhibits apoptosis, thereby attenuating atherogenesis and plaque vulnerability. CTH-H2S may act as a warning biomarker for vulnerable plaque.Abbreviations ATG9A: autophagy related 9A; CTH: cystathionine gamma-lyase; CQ: chloroquine; HASMCs: human aortic smooth muscle cells; H2S: hydrogen sulfide; LAMP1: lysosomal associated membrane protein 1; LAPTM5: lysosomal protein transmembrane 5; NaHS: sodium hydrosulfide hydrate; ox-LDL: oxidized-low density lipoprotein; PPG: DL- propagylglycine; TFEB: transcription factor EB; 3-MA: 3-methyladenine; VSMCs: vascular smooth muscle cells.

Keywords: Autophagy; cystathionine gamma lyase; hydrogen sulfide; plaque stability; transcription factor EB; vascular smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis* / pathology
  • Autophagy
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Biomarkers / metabolism
  • Chloroquine
  • Cystathionine gamma-Lyase / genetics
  • Cystathionine gamma-Lyase / metabolism
  • Gasotransmitters* / metabolism
  • Humans
  • Hydrogen Sulfide* / metabolism
  • Hydrogen Sulfide* / pharmacology
  • Lipoproteins, LDL / metabolism
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism
  • Plaque, Atherosclerotic* / pathology


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Biomarkers
  • Gasotransmitters
  • Lipoproteins, LDL
  • Lysosomal-Associated Membrane Protein 1
  • TFEB protein, human
  • Chloroquine
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide

Grants and funding

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2021-I2M-1-007]; National Natural Science Foundation of China [81800367]; National Natural Science Foundation of China [81825002]; National Natural Science Foundation of China [81870318]; National Key R&D Program of China [2018YFC1312703]; Beijing Outstanding Young Scientist Program [BJJWZYJH01201910023029].