High Circulating Levels of ANGPTL2: Beyond a Clinical Marker of Systemic Inflammation

Abstract

Angiopoietin-like 2 (ANGPTL2) is a proinflammatory protein belonging to the angiopoietin-like family. ANGPTL2 is secreted and detected in the systemic circulation. Different observational clinical studies reported that circulating levels of ANGPTL2 increase significantly in various chronic inflammatory diseases and showed associations between ANGPTL2 levels and diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, these studies did not address the following questions: (a) what are the sources of circulating ANGPTL2? (b) How and by which mechanisms an increase in circulating ANGPTL2 contributes to the pathogenesis of chronic inflammatory diseases? (c) Does an increase in circulating levels of ANGPTL2 measured in a well-defined chronic medical condition originate from a specific cell type? Mechanistic hypotheses have been proposed based on studies performed in mice and cultured cells, and proinflammatory, prooxidative, proangiogenic, proliferative, and antiapoptotic properties of ANGPTL2 have been reported. The aim of this review is to propose answers concerning the potential sources of circulating ANGPTL2 and its common pathological properties associated with various chronic inflammatory diseases and death in humans. We believe that high circulating ANGPTL2 levels are more than an inflammatory marker and may reflect the senescent cellular load of an individual.

Determination of liver fibrosis stages in Egyptian chronic hepatitis B patients by a noninvasive tool

“…Angptl2 also activates the integrin α5β1/Rac1/ NFκB-dependent pathway, subsequently resulting in transcription of several proinflammatory cytokines [20,21]. Angptl2 signaling through integrin a5b1 increases tissue inflammation and ECM remodeling, resulting in activation of tissue remodeling [16,20]. It contributes to the acceleration of tissue fibrosis through activation of the transforming growth factor beta (TGF-β1)/Smad signaling pathway, like in renal fibrosis [22].…”

Association between angiopoietin-like protein 2 and lectin-like oxidized low-density lipoprotein receptor 1 ligand containing apolipoprotein B in patients with type 2 diabetes

“… 1 – 3 Although ANGPTLs cannot bind to angiopoietin receptors such as Tie2 or to the related protein Tie1, 1 , 2 they can regulate angiogenesis similarly to the angiopoietins. 2 , 3 In addition, some ANGPTLs, including ANGPTL3, 4, 6, and 8, also contribute to lipid, glucose, and/or energy metabolism. 1 – 7 …”

“… 2 , 3 In addition, some ANGPTLs, including ANGPTL3, 4, 6, and 8, also contribute to lipid, glucose, and/or energy metabolism. 1 – 7 …”

“… 2 , 3 , 8 Apart from its angiogenic activity, it causes inflammation of adipose tissue in human patients with obesity, resulting in insulin resistance. 2 , 3 , 8 Furthermore, ANGPTL2 can also cause vascular inflammation, 8 endothelial dysfunction, 9 and increased oxidative stress, 10 and it may be associated with tumor metastasis. 11 Although the main sources of circulating ANGPTL2 in humans appear to be adipocytes, endothelial cells, and macrophages that have infiltrated visceral fat tissues, 2 , 3 it can also be secreted by the heart 1 , 12 and by both endothelial cells 13 and macrophages 14 in various other tissues.…”

“… 2 , 3 , 8 Furthermore, ANGPTL2 can also cause vascular inflammation, 8 endothelial dysfunction, 9 and increased oxidative stress, 10 and it may be associated with tumor metastasis. 11 Although the main sources of circulating ANGPTL2 in humans appear to be adipocytes, endothelial cells, and macrophages that have infiltrated visceral fat tissues, 2 , 3 it can also be secreted by the heart 1 , 12 and by both endothelial cells 13 and macrophages 14 in various other tissues. Interestingly, recent studies have demonstrated that the circulating ANGPTL2 level is associated with new-onset type 2 diabetes 15 and with both cardiovascular events and mortality in patients with type 2 diabetes.…”