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Exogenous Hydrogen Sulfide Donors Suppress Neointimal Hyperplasia by Modulating Mitochondrial Dysfunction in Vascular Smooth Muscle Cells.

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Title: Exogenous Hydrogen Sulfide Donors Suppress Neointimal Hyperplasia by Modulating Mitochondrial Dysfunction in Vascular Smooth Muscle Cells.
Authors: He Y; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China., Li C; Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China., Zhang B; International Joint Laboratory of Cerebrovascular Disease of Henan Province, Henan Provincial Engineering Research Center for Cerebrovascular Interventional Innovation, Zhengzhou, 450003, China., Liang J; International Joint Laboratory of Cerebrovascular Disease of Henan Province, Henan Provincial Engineering Research Center for Cerebrovascular Interventional Innovation, Zhengzhou, 450003, China., Si C; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China., Liu Y; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China., Wang Y; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China., Ma C; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China., Li T; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China. dr.litianxiao@zzu.edu.cn., He Y; Cerebrovascular and Neurosurgery Department of Stroke Center, Henan Provincial People's Hospital (Zhengzhou University People's Hospital), Zhengzhou, 450003, China. heyingkun@zzu.edu.cn.; Henan University of Chinese Medicine, Zhengzhou, 450046, China. heyingkun@zzu.edu.cn.
Source: Translational stroke research [Transl Stroke Res] 2026 Sep 25; Vol. 17 (5). Date of Electronic Publication: 2026 Sep 25.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Springer Country of Publication: United States NLM ID: 101517297 Publication Model: Electronic Cited Medium: Internet ISSN: 1868-601X (Electronic) Linking ISSN: 18684483 NLM ISO Abbreviation: Transl Stroke Res Subsets: MEDLINE
Imprint Name(s): Original Publication: New York : Springer
MeSH Terms: Hydrogen Sulfide*/pharmacology , Hydrogen Sulfide*/metabolism , Neointima*/drug therapy , Neointima*/pathology , Neointima*/metabolism , Muscle, Smooth, Vascular*/drug effects , Muscle, Smooth, Vascular*/pathology , Muscle, Smooth, Vascular*/metabolism , Mitochondria*/drug effects , Mitochondria*/metabolism , Myocytes, Smooth Muscle*/drug effects , Myocytes, Smooth Muscle*/metabolism, Hyperplasia/drug therapy ; Reactive Oxygen Species/metabolism ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Organophosphorus Compounds ; Thiones
Abstract: Phenotypic switching of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic is a key factor driving the formation of intracranial atherosclerotic stenosis (ICAS); however, the upstream mitochondrial mechanisms underlying this process and its therapeutic implications remain poorly defined. This study aims to investigate the role and underlying molecular mechanisms of the mitochondria-targeted hydrogen sulfide (H2S) donor AP39 in regulating mitochondrial function during VSMCs phenotypic switching and neointimal hyperplasia. In a platelet-derived growth factor-BB (PDGF-BB)-induced synthetic VSMCs model, mitochondrial function and phenotypic changes were systematically assessed. In vivo, AP39 was locally administered in a mouse carotid artery ligation model to evaluate neointimal formation and vascular remodeling. PDGF-BB induced hypermethylation of the mtDNA D-loop region, ROS accumulation, and Drp1 activation, accompanied by enhanced mitochondrial fission, impaired energy metabolism, and VSMCs phenotypic switching. These alterations were differentially reversed by 5-Aza-dC, NAC, Mdivi-1, or Drp1 silencing. AP39 reduced D-loop methylation and mitochondrial DNMT1 expression, suppressed ROS accumulation and Drp1 activation, preserved mitochondrial structure and oxidative phosphorylation, and attenuated VSMCs phenotypic switching, while partially restoring cystathionine γ-lyase (CSE)-mediated endogenous H₂S production. Consistent with these findings, local AP39 administration in vivo significantly alleviated neointimal hyperplasia following carotid ligation. These results indicate that the mitochondria-targeted H₂S donor AP39 exerts robust vasculoprotective effects through multi-level modulation of D-loop hypermethylation-driven mitochondrial dysfunction, thereby ameliorating ICAS-associated VSMCs phenotypic switching and neointimal hyperplasia. This study provides a novel mechanistic framework and highlights a potential mitochondria-targeted therapeutic strategy for vascular remodeling in ICAS.
(© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Competing Interests: Declarations. Animal Ethics: All animal experiments were conducted in strict accordance with national regulations and guidelines for the care and use of laboratory animals. The experimental protocols were reviewed and approved by the Animal Ethics Committee of Zhengzhou University (approval No. ZZU-LAC20240802), and all procedures complied with approved ethical standards. Competing Interests: The authors declare no competing interests.
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Grant Information: SBGJ202303001 Henan Provincial Medical Science and Technology Research Program; GWJJ2023100101 Capacity Building and Continuing Education Program of the National Health Commission; 8257072246 National Natural Science Foundation of China; 241111313200 Henan Provincial Key Research and Development Program; 252300421604 Henan Provincial Youth Science Foundation
Contributed Indexing: Keywords: AP39; Mitochondrial Dysfunction; Neointima Hyperplasia; Phenotypic Switching; Vascular Smooth Muscle Cells
Substance Nomenclature: YY9FVM7NSN (Hydrogen Sulfide)
0 (AP39 compound)
0 (Reactive Oxygen Species)
0 (Organophosphorus Compounds)
0 (Thiones)
Entry Date(s): Date Created: 20260925 Date Completed: 20260925 Latest Revision: 20261022
Update Code: 20261023
DOI: 10.1007/s12975-026-01495-w
PMID: 42789138
Database: MEDLINE
Description
ISSN:1868-601X
DOI:10.1007/s12975-026-01495-w