The Role of Hydrogen Sulfide in Plaque Stability

Abstract

Atherosclerosis is the greatest contributor to cardiovascular events and is involved in the majority of deaths worldwide. Plaque rapture or erosion precipitates life-threatening thrombi, resulting in the obstruction blood flow to the heart (acute coronary syndrome), brain (ischemic stroke) or low extremities (peripheral vascular diseases). Among these events, major causation dues to the plaque rupture. Although the initiation, procession, and precise time of controlling plaque rupture are unclear, foam cell formation and apoptosis, cell death, extracellular matrix components, protease expression and activity, local inflammation, intraplaque hemorrhage, and calcification contribute to the plaque instability. These alterations tightly associate with the function regulation of intraplaque various cell populations. Hydrogen sulfide (H₂S) is gasotransmitter derived from methionine metabolism and exerts a protective role in the genesis of atherosclerosis. Recent progress also showed H₂S mediated the plaque stability. In this review, we discuss the progress of endogenous H₂S modulation on functions of vascular smooth muscle cells, monocytes/macrophages, and T cells, and the molecular mechanism in plaque stability.

Keywords: atherosclerosis; cystathionine gamma lyase; hydrogen sulfide; plaque stability.

Figure 1

The schematic diagram of endogenous CSE/H₂S biological modulation and molecular mechanism in VSMC proliferation, apoptosis, ferroptosis, autophagy, phage-like differentiation, osteochondrogenic conversion/calcification, collagen synthesis/secretion, matrix protease expression and activity, engage in the pathogenesis of atherosclerotic plaque and its stability regulation. Foxo1: forkhead box O1; ERK: Extracellular signal-regulated kinase Stat3: signal transducer and activator of transcription 3; Pdha1: pyruvate dehydrogenase E1 alpha 1; Brg-1: brahma-related gene 1; Lox-1: oxidized low density lipoprotein receptor 1; Runx2: runt related transcription factor 2; Nqo1: NAD(P)H quinone dehydrogenase1; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor (erythroid-derived 2)-like 2; GSH: glutathione; Gpx4: glutathione peroxidase 4; Tfeb: transcription factor EB.

Figure 2

The schematic diagram of CSE/H₂S modulation in macrophages polarization, macrophage-derived foam cell formation and efferocytosis, and then participation in the plaque stability. PI3K: phosphatidylinositol 3-kinase; TLR4: toll-like receptor 4; Sirt1: sirtuin 1; ABCA1: ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; SR-A: scavenger receptor A; LXR: liver X receptor; HO1: heme oxygenase 1; TXNRD1: thioredoxin reductase 1; SRXN1: sulfiredoxin-1; JMJD3: jumonji domain-containing protein 3; PPARγ: peroxisome proliferator activated receptor gamma; ACAT-1: acyl-coenzyme A cholesterol acyltransferase-1; NOX4: NADPH oxidase 4; ROS: reactive oxidant species; CX3CR1: chemokine (C-X3-C motif) receptor 1; CX3CL1: chemokine (C-X3-C motif) ligand 1; LRP1: LDL receptor related protein 1; IL-1β: interleukin 1 beta; IL-4: interleukin 4; IL-6: interleukin 6; IL-10: interleukin 10; IL-13: interleukin 13; TNFα: tumor necrosis factor alpha.