Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis
Abstract 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 form...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412498 |
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| author | Yu Cao Qirong Xie Qiang Zheng Jingping Zhang Mengyu Yao Zhongyong Du Lujun Zhang Tianyang Hu Yunli Zhao Jianlin Du Yongyong Li Yuxing Feng ND Melgiri Xiaodong Zhao Rongzhong Huang Yang Sun |
| author_facet | Yu Cao Qirong Xie Qiang Zheng Jingping Zhang Mengyu Yao Zhongyong Du Lujun Zhang Tianyang Hu Yunli Zhao Jianlin Du Yongyong Li Yuxing Feng ND Melgiri Xiaodong Zhao Rongzhong Huang Yang Sun |
| author_sort | Yu Cao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-c9875bc422c2426bbd86c48c4a19c4d5 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-c9875bc422c2426bbd86c48c4a19c4d52025-08-20T02:34:47ZengWileyAdvanced Science2198-38442025-05-011218n/an/a10.1002/advs.202412498Macrophage HM13/SPP Enhances Foamy Macrophage Formation and AtherogenesisYu Cao0Qirong Xie1Qiang Zheng2Jingping Zhang3Mengyu Yao4Zhongyong Du5Lujun Zhang6Tianyang Hu7Yunli Zhao8Jianlin Du9Yongyong Li10Yuxing Feng11ND Melgiri12Xiaodong Zhao13Rongzhong Huang14Yang Sun15Department of Cardiovascular Surgery the First People’s Hospital of Yunnan Province No. 157, Jinbi Road, Xishan District Kunming Yunnan 650032 ChinaDepartment of Ultrasound Chongqing Key Laboratory of Ultrasound Molecular Imaging the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaDepartment of Cardiovascular Surgery the First People’s Hospital of Yunnan Province No. 157, Jinbi Road, Xishan District Kunming Yunnan 650032 ChinaDepartment of Hematopathology the First People's Hospital of Yunnan Province No. 157, Jinbi Road, Xishan District Kunming Yunnan 650032 ChinaDepartment of Cardiovascular Surgery the First People’s Hospital of Yunnan Province No. 157, Jinbi Road, Xishan District Kunming Yunnan 650032 ChinaDepartment of Cardiovascular Surgery the First People’s Hospital of Yunnan Province No. 157, Jinbi Road, Xishan District Kunming Yunnan 650032 ChinaPrecision Medicine Center the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaPrecision Medicine Center the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaPrecision Medicine Center the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaDepartment of Cardiology the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaDepartment of Geriatric Medicine the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaDepartment of Rehabilitation and Pain Medicine the Ninth People's Hospital of Chongqing No. 69, Jialing Village, Beibei District Chongqing 400700 ChinaImpactys Foundation for Biomedical Research 10300 Campus Pointe Drive San Diego CA 92121 USAPrecision Medicine Center the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaPrecision Medicine Center the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaDepartment of Ultrasound Chongqing Key Laboratory of Ultrasound Molecular Imaging the Second Affiliated Hospital of Chongqing Medical University No. 76, Linjiang Road, Yuzhong District Chongqing 400010 ChinaAbstract 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.https://doi.org/10.1002/advs.202412498AIPatherosclerosisfoamy macrophageHM13HO‐1macrophage |
| spellingShingle | Yu Cao Qirong Xie Qiang Zheng Jingping Zhang Mengyu Yao Zhongyong Du Lujun Zhang Tianyang Hu Yunli Zhao Jianlin Du Yongyong Li Yuxing Feng ND Melgiri Xiaodong Zhao Rongzhong Huang Yang Sun Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis Advanced Science AIP atherosclerosis foamy macrophage HM13 HO‐1 macrophage |
| title | Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis |
| title_full | Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis |
| title_fullStr | Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis |
| title_full_unstemmed | Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis |
| title_short | Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis |
| title_sort | macrophage hm13 spp enhances foamy macrophage formation and atherogenesis |
| topic | AIP atherosclerosis foamy macrophage HM13 HO‐1 macrophage |
| url | https://doi.org/10.1002/advs.202412498 |
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