ANGPTL2, or Angiopoietin-like protein 2, is a pro-inflammatory protein belonging to the angiopoietin-like family. It is secreted into the systemic circulation and is involved in multiple biological processes. It has been associated with pathways such as NF-κB, which is related to inflammation, and integrin α5β1 and LILRB2-mediated signaling [5,6]. ANGPTL2 has diverse functions including roles in tissue repair, remodeling, and potentially in the regulation of oligodendrocyte differentiation through binding to MAG [5,7].

In various disease models, ANGPTL2 has been shown to have significant impacts. In a mouse model of ICI-related autoimmune myocarditis, ANGPTL2 deficiency attenuated autoimmune inflammation, associated with decreased T cells and macrophages, indicating its role in promoting inflammation [1]. In doxorubicin-induced cardiotoxicity, ANGPTL2 overexpression exacerbated cardiac dysfunction, while its knockdown alleviated the condition by suppressing the DUSP1 pathway [2]. In LPS-induced septic cardiomyopathy, ANGPTL2 overexpression aggravated cardiac impairment and inflammation, and its silence had the opposite effect, acting via the NLRP3-mediated inflammasome in a DUSP1-dependent pathway [4]. In acute lung injury, ANGPTL2 knockdown in mice alleviated pathological symptoms, reduced inflammation, and regulated alveolar macrophage polarization [3].

In summary, ANGPTL2 plays important roles in inflammation, cardiac function, and immune-related processes. Gene knockout (KO) and conditional knockout (CKO) mouse models have been crucial in revealing its function in diseases such as autoimmune myocarditis, cardiotoxicity, septic cardiomyopathy, and acute lung injury, providing insights into potential therapeutic targets for these conditions.

References:

1. Horiguchi, Haruki, Kadomatsu, Tsuyoshi, Yamashita, Tomoya, Miyata, Keishi, Oike, Yuichi. 2023. ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis. In Communications biology, 6, 965. doi:10.1038/s42003-023-05338-4. https://pubmed.ncbi.nlm.nih.gov/37736764/

2. Liu, Cheng, Chen, Qiuling, Liu, Huadong. . ANGPTL2 aggravates doxorubicin-induced cardiotoxicity via inhibiting DUSP1 pathway. In Bioscience, biotechnology, and biochemistry, 86, 1631-1640. doi:10.1093/bbb/zbac156. https://pubmed.ncbi.nlm.nih.gov/36107816/

3. Yang, Fan, Chen, Muhu, Liu, Ying, Yu, Youwei, Deng, Lu. . ANGPTL2 knockdown induces autophagy to relieve alveolar macrophage pyroptosis by reducing LILRB2-mediated inhibition of TREM2. In Journal of cellular and molecular medicine, 28, e18280. doi:10.1111/jcmm.18280. https://pubmed.ncbi.nlm.nih.gov/38758159/

4. Li, Jun, Wan, Ting, Liu, Cheng, Ke, Dong, Li, Luocheng. 2023. ANGPTL2 aggravates LPS-induced septic cardiomyopathy via NLRP3-mediated inflammasome in a DUSP1-dependent pathway. In International immunopharmacology, 123, 110701. doi:10.1016/j.intimp.2023.110701. https://pubmed.ncbi.nlm.nih.gov/37531825/

5. Nishiyama, Sayuri, Hirose, Naoto, Yanoshita, Makoto, Asakawa-Tanne, Yuki, Tanimoto, Kotaro. 2021. ANGPTL2 Induces Synovial Inflammation via LILRB2. In Inflammation, 44, 1108-1118. doi:10.1007/s10753-020-01406-7. https://pubmed.ncbi.nlm.nih.gov/33538932/

6. Thorin-Trescases, Nathalie, Thorin, Eric. 2017. High Circulating Levels of ANGPTL2: Beyond a Clinical Marker of Systemic Inflammation. In Oxidative medicine and cellular longevity, 2017, 1096385. doi:10.1155/2017/1096385. https://pubmed.ncbi.nlm.nih.gov/29138671/

7. Chen, Lu, Yu, Zhuo, Xie, Li, Zheng, Junke, Zhang, Yaping. 2023. ANGPTL2 binds MAG to efficiently enhance oligodendrocyte differentiation. In Cell & bioscience, 13, 42. doi:10.1186/s13578-023-00970-3. https://pubmed.ncbi.nlm.nih.gov/36855057/