Cao Yu, Xie Qirong, Zheng Qiang, Zhang Jingping, Yao Mengyu, Du Zhongyong, Zhang Lujun, Hu Tianyang, Zhao Yunli, Du Jianlin, Li Yongyong, Feng Yuxing, Melgiri N D, Zhao Xiaodong, Huang Rongzhong, Sun Yang
Department of Cardiovascular Surgery, the First People's Hospital of Yunnan Province, No. 157, Jinbi Road, Xishan District, Kunming, Yunnan, 650032, China.
Center for Translational Research in Clinical Medicine, the Affiliated Hospital of Kunming University of Science and Technology, No. 68, Wenchang Road, Wuhua District, Kunming, Yunnan, 650093, China.
Adv Sci (Weinh). 2025 May;12(18):e2412498. doi: 10.1002/advs.202412498. Epub 2025 Mar 20.
Aryl Hydrocarbon Receptor-Interacting Protein (AIP) reduces macrophage cholesterol-ester accumulation and may prevent atherogenic foamy macrophage formation. Analyzing AIP-associated regulatory gene networks can aid in identifying key regulatory mechanism(s) underlying foamy macrophage formation. A weighted gene co-expression network analysis on the Stockholm Atherosclerosis Gene Expression (STAGE) patient cohort identifies AIP as a negative correlate of Histocompatibility Minor 13 (HM13), which encodes the ER-associated degradation (ERAD) protein Signal Peptide Peptidase (HM13/SPP). The negative correlation between AIP and HM13/SPP on mRNA and protein levels is validated in oxLDL-stimulated macrophages and human plaque foamy macrophages. Mechanistically, AIP, via its chaperone interaction with Aryl Hydrocarbon Receptor (AHR), inhibits p38-c-JUN-mediated HM13 transactivation, thereby suppressing macrophage lipid accumulation. Myeloid HM13/SPP overexpression enhances oxLDL-induced foamy macrophage formation in vitro as well as atherogenesis and plaque foamy macrophage load in vivo, while myeloid HM13/SPP knockout produces the opposite effects. Mechanistically, myeloid HM13/SPP enhances oxLDL-induced foamy macrophage formation in vitro as well as atherogenesis and plaque foamy macrophage load in vivo via promoting ERAD-mediated proteasomal degradation of the metabolic regulator Heme Oxygenase-1 (HO-1). In conclusion, AIP downregulates macrophage HM13/SPP, a driver of oxLDL-induced lipid loading, foamy macrophage generation, and atherogenesis.
芳烃受体相互作用蛋白（AIP）可减少巨噬细胞胆固醇酯的积累，并可能预防致动脉粥样硬化的泡沫巨噬细胞形成。分析与AIP相关的调控基因网络有助于识别泡沫巨噬细胞形成背后的关键调控机制。对斯德哥尔摩动脉粥样硬化基因表达（STAGE）患者队列进行的加权基因共表达网络分析确定AIP与组织相容性微小抗原13（HM13）呈负相关，HM13编码内质网相关降解（ERAD）蛋白信号肽肽酶（HM13/SPP）。在氧化型低密度脂蛋白（oxLDL）刺激的巨噬细胞和人类斑块泡沫巨噬细胞中，AIP与HM13/SPP在mRNA和蛋白质水平上的负相关得到了验证。从机制上讲，AIP通过其与芳烃受体（AHR）的伴侣相互作用，抑制p38-c-JUN介导的HM13反式激活，从而抑制巨噬细胞脂质积累。髓系HM13/SPP过表达增强了体外oxLDL诱导的泡沫巨噬细胞形成以及体内动脉粥样硬化和斑块泡沫巨噬细胞负荷，而髓系HM13/SPP基因敲除则产生相反的效果。从机制上讲，髓系HM13/SPP通过促进ERAD介导的代谢调节因子血红素加氧酶-1（HO-1）的蛋白酶体降解，增强了体外oxLDL诱导的泡沫巨噬细胞形成以及体内动脉粥样硬化和斑块泡沫巨噬细胞负荷。总之，AIP下调巨噬细胞HM13/SPP，HM13/SPP是oxLDL诱导的脂质负荷、泡沫巨噬细胞生成和动脉粥样硬化的驱动因子。
