Zhuang Xinghui, Zarif Mohammad, Shen Yue, Zhang Zhaofeng, He Jian, Xie Linfeng, Wu Qingsong, Lin Xinfan, Chen Keyuan, Tian Yue, Lin Yong, Zhang Yuling, Cai Ziwen, Qiu Zhihuang, Chen Liangwan
Department of Cardiovascular Surgery Fujian Medical University Union Hospital Fuzhou China.
Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University) Fujian Province University Fuzhou China.
J Am Heart Assoc. 2025 Feb 4;14(3):e037172. doi: 10.1161/JAHA.124.037172. Epub 2025 Jan 23.
Apolipoprotein C3 (apo C3) is primarily secreted by the liver and is involved in promoting sterile inflammation and organ damage under pathological conditions. Previous studies have shown that apo C3 is abundant in the plasma exosomes of patients with aortic dissection (AD), but its specific role in AD remains unclear.
In vivo, adeno-associated virus was used to knock down hepatic apo C3 expression in an AD mouse model to assess the impact of liver-derived apo C3 on the development of AD. In vitro, recombinant apo C3 protein was added to the culture medium of J774A.1 macrophages to evaluate its effect on macrophage polarization and to identify the underlying mechanisms. Additionally, the effect of apo C3 on the function of aortic endothelial and smooth muscle cells was explored. Apo C3 in the aortas of AD mice was found to originate from abnormal hepatic secretion, which enters the bloodstream and subsequently deposits in the aorta. Adeno-associated virus-mediated hepatic apo C3 knockdown significantly reduced AD incidence (=0.0036), macrophage infiltration (=0.0004), and collagen deposition in the aorta (=0.0016). Similarly, inhibiting the apo C3 receptor Toll-like receptor 2 significantly lowered AD incidence (=0.0352). In vitro, recombinant apo C3 protein promoted M1 polarization and matrix metalloproteinase secretion in macrophages by activating the Toll-like receptor 2/NLR family pyrin domain containing 3 pathway. Additionally, apo C3 increased adhesion molecule expression in endothelial cells and induced inflammation, chemotaxis, and apoptosis in vascular smooth muscle cells.
Our findings highlight the role of abnormally secreted hepatic apo C3 in promoting aortic inflammation.
载脂蛋白C3（apo C3）主要由肝脏分泌，在病理条件下参与促进无菌性炎症和器官损伤。先前的研究表明，apo C3在主动脉夹层（AD）患者的血浆外泌体中含量丰富，但其在AD中的具体作用仍不清楚。
在体内，利用腺相关病毒敲低AD小鼠模型中肝脏apo C3的表达，以评估肝脏来源的apo C3对AD发展的影响。在体外，将重组apo C3蛋白添加到J774A.1巨噬细胞的培养基中，以评估其对巨噬细胞极化的影响并确定潜在机制。此外，还探讨了apo C3对主动脉内皮细胞和平滑肌细胞功能的影响。发现AD小鼠主动脉中的apo C3源自肝脏异常分泌，其进入血液后随后沉积在主动脉中。腺相关病毒介导的肝脏apo C3敲低显著降低了AD发病率（=0.0036）、巨噬细胞浸润（=0.0004）和主动脉中的胶原沉积（=0.0016）。同样，抑制apo C3受体Toll样受体2显著降低了AD发病率（=0.0352）。在体外，重组apo C3蛋白通过激活Toll样受体2/NLR家族含pyrin结构域蛋白3途径促进巨噬细胞中的M1极化和基质金属蛋白酶分泌。此外，apo C3增加了内皮细胞中黏附分子的表达，并诱导血管平滑肌细胞发生炎症、趋化和凋亡。
我们的研究结果突出了异常分泌的肝脏apo C3在促进主动脉炎症中的作用。
