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SP2509 functions as a novel ferroptosis inhibitor by reducing intracellular iron level in vascular smooth muscle cells.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2024 Jul; Vol. 219, pp. 49-63. Date of Electronic Publication: 2024 Apr 10. - Publication Year :
- 2024
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Abstract
- Previous studies have shown that ferroptosis of vascular smooth muscle cells (VSMCs) is involved in the development of aortic dissection (AD) and that histone methylation regulates this process. SP2509 acts as a specific inhibitor of lysine-specific demethylase 1 (LSD1), which governs a variety of biological processes. However, the effect of SP2509 on VSMC ferroptosis and AD remains to be elucidated. This aim of this study was to investigate the role and underlying mechanism of SP2509-mediated histone methylation on VSMC ferroptosis. Here, a mouse model of AD was established, and significantly reduced levels of H3K4me1 and H3K4me2 (target of SP2509) were found in the aortas of AD mice. In VSMCs, SP2509 treatment led to a dose-dependent increase in H3K4me2 levels. Furthermore, we found that SP2509 provided equivalent protection to ferrostatin-1 against VSMC ferroptosis, as evidenced by increased cell viability, decreased cell death and lipid peroxidation. RNA-sequencing analysis and subsequent experiments revealed that SP2509 counteracted cystine deficiency-induced response to inflammation and oxidative stress. More importantly, we demonstrated that SP2509 inhibited the expression of TFR and ferritin to reduce intracellular iron levels, thereby effectively blocking the process of ferroptosis. Therefore, our findings indicate that SP2509 protects VSMCs from multiple stimulus-induced ferroptosis by reducing intracellular iron levels, thereby preventing lipid peroxidation and cell death. These findings suggest that SP2509 may be a promising drug to alleviate AD by reducing iron deposition and VSMC ferroptosis.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Oxidative Stress drug effects
Humans
Disease Models, Animal
Lipid Peroxidation drug effects
Phenylenediamines pharmacology
Male
Cell Survival drug effects
Histones metabolism
Histones genetics
Histone Demethylases metabolism
Histone Demethylases genetics
Mice, Inbred C57BL
Cyclohexylamines
Ferroptosis drug effects
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular pathology
Iron metabolism
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 219
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38608823
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2024.04.220