Dong Qianqian, Liu Fang, Zhu Jiahui, Li Mingxi, Chen An, Feng Liyun, Lan Zirong, Ye Yuanzhi, Lu Lihe, Liang Qingchun, Yan Jianyun
Department 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.
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, China.
Eur J Pharmacol. 2024 Dec 15;985:177122. doi: 10.1016/j.ejphar.2024.177122. Epub 2024 Nov 10.
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 VitD-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 VitD-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.
血管钙化常见于慢性肾脏病（CKD）、糖尿病和高血压等慢性病患者中，是心血管事件的重要原因。因此，确定有效的治疗靶点以抑制血管钙化的进展至关重要。衣康酸4-辛酯（4-OI）是衣康酸的衍生物，具有抗炎和抗氧化活性，这两者在血管钙化进展中均起重要作用。然而，4-OI在血管钙化中的作用及分子机制尚未阐明。在本研究中，我们使用血管平滑肌细胞（VSMC）、动脉环和小鼠研究了外源性4-OI对血管钙化的影响。茜素红染色和蛋白质印迹显示，4-OI抑制人VSMC的钙化和成骨分化。同样，4-OI抑制大鼠和人动脉环以及维生素D超载小鼠主动脉的钙化。从机制上讲，RNA测序分析显示，4-OI处理最有可能影响血红素加氧酶1（HMOX-1）mRNA表达。该研究表明，4-OI处理可增加HMOX-1 mRNA和蛋白质水平，但在成骨条件下抑制VSMC中的炎症和氧化应激。此外，通过siRNA敲低HMOX-1或用HMOX-1抑制剂ZnPP9处理可显著逆转4-OI对维生素D超载小鼠VSMC和主动脉钙化的抑制作用。此外，通过siRNA敲低HMOX-1可明显消除4-OI对VSMC中炎症的抑制作用。这些发现表明，4-OI通过调节HMOX-1减轻血管钙化并抑制氧化应激和炎症，表明其作为血管钙化治疗靶点的潜力。
