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SP2509 functions as a novel ferroptosis inhibitor by reducing intracellular iron level in vascular smooth muscle
Yi He1, Xingbo Wang1, Siqi Chen1
1Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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.
Insights
SP2509, an LSD1 inhibitor, prevents ferroptosis in vascular smooth muscle cells (VSMCs) by reducing iron levels. This offers a potential treatment for aortic dissection (AD) by mitigating VSMC death and lipid peroxidation.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Cell Death Mechanisms
Background:
- Ferroptosis of vascular smooth muscle cells (VSMCs) contributes to aortic dissection (AD).
- Histone methylation, regulated by lysine-specific demethylase 1 (LSD1), plays a role in this process.
- The impact of SP2509, an LSD1 inhibitor, on VSMC ferroptosis and AD requires investigation.
Purpose of the Study:
- To investigate the role of SP2509-mediated histone methylation in VSMC ferroptosis.
- To elucidate the underlying mechanism of SP2509's effects on ferroptosis.
- To assess SP2509's therapeutic potential in a mouse model of AD.
Main Methods:
- Established a mouse model of aortic dissection (AD).
- Treated VSMCs with SP2509 and measured histone methylation levels (H3K4me1, H3K4me2).
- Assessed VSMC viability, cell death, lipid peroxidation, and iron levels.
- Utilized RNA-sequencing to analyze gene expression changes.
Main Results:
- AD mice exhibited reduced H3K4me1 and H3K4me2 levels.
- SP2509 treatment increased H3K4me2 in VSMCs and protected against ferroptosis.
- SP2509 inhibited cystine deficiency-induced inflammation and oxidative stress.
- SP2509 reduced transferrin receptor (TFR) and ferritin expression, lowering intracellular iron and blocking ferroptosis.
Conclusions:
- SP2509 protects VSMCs from ferroptosis by decreasing intracellular iron levels.
- SP2509 mitigates lipid peroxidation and cell death, offering protection against AD.
- SP2509 demonstrates potential as a therapeutic agent for AD by targeting iron deposition and VSMC ferroptosis.
