The therapeutic potential of hydrogen sulfide and its donors, a new discovery in vascular diseases

Abstract

Hydrogen sulfide (H 2 S), an important gaseous signaling molecule, plays a critical role in maintaining vascular homeostasis. H 2 S participates in numerous biological functions, including redox regulation, interactions with other signaling molecules, and post-translational modifications of proteins through sulfhydration. Additionally, H 2 S influences key pathological processes such as inflammation, oxidative stress, and cell apoptosis. Dysregulation of endogenous H 2 S metabolism has been closely linked to the development of various vascular diseases, including aortic aneurysms, aortic dissection, atherosclerosis, and thrombotic conditions. Various endogenous and exogenous H 2 S donors have been developed, and these donors have demonstrated promising effects in preclinical models of vascular diseases such as atherosclerosis, pulmonary hypertension, and thrombosis by modulating oxidative stress, inflammatory pathways, and vascular remodeling. This review consolidates the current knowledge on the effects of H 2 S on vascular function and offers a comprehensive summary of recent advancements in the development and application of H 2 S donors in vascular disease research.

Keywords: Biological functions; Clinical application; Hydrogen sulfide; Pathological processes; Vascular diseases.

FIGURE 1.

Biosynthesis and transformation of H₂S in mammalian cells. CAT, cysteine aminotransferase; TMT, thiol methyltransferase.

FIGURE 2.

The role of different proteins in the cardiovascular system after S-sulfhydration. After protein S-sulfhydration, it exerts antioxidative stress in the cardiovascular system, restores ER homeostasis, regulates ion channels, promotes vasodilation, and regulates glucose and lipid metabolism. IGF1R, Insulin-like growth factor-1 receptor; Keap-1, Kelch-like ECH-associated protein1; Kir6.1, ATP-sensitive potassium channel 6.1; MEK1, mitogen-activated extracellular signal-regulated kinase 1; Nrf2, nuclear factor E2-related factor 2; PARP-1, poly (ADPribose) polymerase-1; PPARγ, peroxisome proliferator-activated receptor γ; PTP1B, protein tyrosine phosphatase 1B; SP1, specific protein-1; TRPV, transient receptor potential family member; VEGFR2, vascular endothelial growth factor receptor 2.

FIGURE 3.

Application of various H₂S donors in vascular diseases. CSE/CTH, cystathionine-γ-lyase; GYY4137, morpholine thiophosphate; NaHS, sodium hydrosulfide; Na₂S, sodium sulfide; ACS14, H(2)S-releasing aspirin derivative; PGE2, prostaglandin E2; HSD-R, H₂S donor-ROS; ALG-TA-APTC, an ADSCs-loaded hydrogel with properties of conductivity and controllable H₂S releasing behavior; STS, sodium thiosulfate; SA/JK-1, a functional sodium alginate (SA) by incorporating JK-1 molecules, a pH-dependent H₂S donor, into the SA sponge; P-N bio-HJ, P-N bioheterojunction (bio-HJ) material composed of p-type copper sulfide (p-CuS), n-type bismuth sulfide (n-Bi₂S₃), and lactate oxidase (LOx); CuFe₂S₃@LOD, a hydrogen sulfide-releasing alternately catalytic bioheterojunction enzyme (AC-BioHJzyme), which composed of CuFe₂S₃ and lactate oxidase (LOD); PSA@ADT-OH, photothermal H₂S nanogenerator by coassembling a photosensitizer agent (PSA) with the H₂S donor 5-p-hydroxyphenyl-3H-1,2-dithiole-3-thione(ADT-OH).