Angptl2, short for Angiopoietin-like protein 2, is a secreted glycoprotein and a member of the angiopoietin-like protein family. It has been implicated in numerous physiological and pathological functions, including angiogenesis, hematopoiesis, and inflammation. It is involved in multiple signaling pathways such as the NF-κB pathway [1,2,3,4,5,6,7], integrin α5β1-mediated pathways [4,5], and the DUSP1-related pathways [3,7]. Dysregulation of Angptl2 has been associated with various diseases, highlighting its biological importance. Genetic models, especially KO/CKO mouse models, have been crucial in understanding its functions.

In a mouse model of ICI-related autoimmune myocarditis, Angptl2 deficiency attenuated autoimmune inflammation, associated with decreased T cells and macrophages. Cardiac myofibroblast-derived Angptl2 enhanced chemoattractant expression via the NF-κB pathway, accelerating T cell recruitment into heart tissues [1]. In the context of aging-related heart diseases, prolonged Angptl2 autocrine/paracrine signaling in vascular tissue led to chronic inflammation and pathologic tissue remodeling, accelerating CVD development. Conversely, Angptl2 inactivation in vascular tissue and the heart delayed the development or progression of CVD and HF [2]. In doxorubicin-induced cardiotoxicity, cardiac-specific Angptl2 overexpression exacerbated cardiac dysfunction, while knockdown alleviated it, with the mechanism involving the DUSP1 pathway [3]. In LPS-induced septic cardiomyopathy, Angptl2 overexpression aggravated, and knockdown ameliorated, cardiac impairment and inflammation, via a DUSP1-dependent activation of the NLRP3 inflammasome [7].

In conclusion, Angptl2 plays significant roles in inflammation, heart diseases, and other pathological conditions. Studies using KO/CKO mouse models have revealed its contributions to the development and progression of ICI-related autoimmune myocarditis, aging-related heart diseases, doxorubicin-induced cardiotoxicity, and septic cardiomyopathy. These findings provide insights into the underlying mechanisms and potential therapeutic targets for these diseases.