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Updated: Jun 7, 2025
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling
Qianqian Dong1, Fang Liu1, Jiahui Zhu1
1Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, China.
Abstract:
Vascular calcification frequently occurs in patients with chronic conditions such as chronic kidney disease (CKD), diabetes, and hypertension and represents a significant cause of cardiovascular events. Thus, identifying effective therapeutic targets to inhibit the progression of vascular calcification is essential. 4-Octyl itaconate (4-OI), a derivative of itaconate, exhibits anti-inflammatory and antioxidant activity, both of which play an essential role in the progression of vascular calcification. However, the role and molecular mechanisms of 4-OI in vascular calcification have not yet been elucidated. In this study, we investigated the effects of exogenous 4-OI on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings, and mice. Alizarin red staining and western blot revealed that 4-OI inhibited calcification and osteogenic differentiation of human VSMCs. Similarly, 4-OI inhibited calcification of rat and human arterial rings and VitD3-overloaded mouse aortas. Mechanistically, RNA sequencing analysis revealed that 4-OI treatment is most likely to affect heme oxygenase 1 (HMOX-1) mRNA expression. The study demonstrated that 4-OI treatment increased HMOX-1 mRNA and protein levels, but suppressed inflammation and oxidative stress in VSMCs under osteogenic conditions. Moreover, HMOX-1 knockdown by siRNA or treatment with the HMOX-1 inhibitor ZnPP9 significantly reversed the suppression effect on calcification of VSMCs and aortas of VitD3-overloaded mice by 4-OI. Furthermore, HMOX-1 knockdown by siRNA markedly abrogated the inhibitory effect of 4-OI on inflammation in VSMCs. These findings suggest that 4-OI alleviates vascular calcification and inhibits oxidative stress and inflammation through modulation of HMOX-1, indicating its potential as a therapeutic target for vascular calcification.
Insights
4-Octyl itaconate (4-OI) reduces vascular calcification by inhibiting inflammation and oxidative stress. This effect is mediated through the heme oxygenase 1 (HMOX-1) pathway, suggesting 4-OI as a potential therapeutic target.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Vascular calcification is a significant contributor to cardiovascular events in chronic diseases like CKD, diabetes, and hypertension.
- Identifying therapeutic targets to inhibit vascular calcification is crucial for patient outcomes.
- 4-Octyl itaconate (4-OI), a novel itaconate derivative, possesses anti-inflammatory and antioxidant properties, yet its role in vascular calcification remains unclear.
Purpose of the Study:
- To investigate the therapeutic potential of 4-Octyl itaconate (4-OI) in mitigating vascular calcification.
- To elucidate the underlying molecular mechanisms by which 4-OI affects vascular calcification, inflammation, and oxidative stress.
Main Methods:
- Utilized human vascular smooth muscle cells (VSMCs), arterial rings, and a mouse model of vascular calcification.
- Assessed calcification and osteogenic differentiation using Alizarin red staining and Western blot.
- Employed RNA sequencing to identify molecular targets of 4-OI.
- Investigated the role of heme oxygenase 1 (HMOX-1) using siRNA knockdown and specific inhibitors.
Main Results:
- 4-Octyl itaconate (4-OI) significantly inhibited VSMC calcification and osteogenic differentiation.
- 4-OI demonstrated protective effects against calcification in arterial rings and mouse aortas.
- RNA sequencing identified heme oxygenase 1 (HMOX-1) as a key mediator, with 4-OI upregulating HMOX-1 expression.
- 4-OI suppressed inflammation and oxidative stress in VSMCs, effects dependent on HMOX-1 activity.
- HMOX-1 knockdown reversed the anti-calcification and anti-inflammatory effects of 4-OI.
Conclusions:
- 4-Octyl itaconate (4-OI) effectively alleviates vascular calcification.
- The therapeutic benefits of 4-OI are attributed to its ability to inhibit oxidative stress and inflammation via the HMOX-1 pathway.
- 4-OI represents a promising therapeutic candidate for managing vascular calcification.
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