Hostname: page-component-848d4c4894-ndmmz Total loading time: 0 Render date: 2024-06-06T07:33:25.266Z Has data issue: false hasContentIssue false
  • English
  • Français

Angiopoietin-like-2: a multifaceted protein with physiological and pathophysiological properties

Published online by Cambridge University Press:  24 November 2014

Nathalie Thorin-Trescases  and
Eric Thorin
Nathalie Thorin-Trescases*
Affiliation:
Faculty of Medicine, Montreal Heart Institute, Research Center, University of Montreal, Montreal, Canada
Eric Thorin
Affiliation:
Faculty of Medicine, Montreal Heart Institute, Research Center, University of Montreal, Montreal, Canada Department of Surgery, Montreal, Canada.
*
*Corresponding author: Nathalie Thorin-Trescases, Montreal Heart Institute, Research Center, 5000 rue Bélanger Est, H1 T 1C8, Montreal, Quebec, Canada. E-mail: nathalie.trescases@icm-mhi.org
Get access Rights & Permissions [Opens in a new window]

Abstract

Angptl2 is a multifaceted protein, displaying both physiological and pathological functions, in which scientific and clinical interest is growing exponentially within the past few years. Its physiological functions are not well understood, but angptl2 was first acknowledged for its pro-angiogenic and antiapoptotic capacities. In addition, angptl2 can be considered a growth factor, since it increases survival and expansion of hematopoietic stem cells and may promote vasculogenesis. Finally, angptl2 has an important, but largely unrecognised, physiological role: in the cytosol, angptl2 binds to type 1A angiotensin II receptors and induces their recycling, with recovery of the receptor signal functions. Despite these important physiological properties, angptl2 is better acknowledged for its deleterious pro-inflammatory properties and its contribution in multiple chronic diseases such as cancer, diabetes, atherosclerosis, metabolic disorders and many other chronic diseases. This review aims at presenting an updated description of both the beneficial and deleterious biological properties of angptl2, in addition to its molecular signalling pathways and transcriptional regulation. The multiplicity of diseases in which angptl2 contributes makes it a new highly relevant clinical therapeutic target.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e17
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Kim, I. et al. (1999) Molecular cloning, expression, and characterization of angiopoietin-related protein. angiopoietin-related protein induces endothelial cell sprouting. Journal of Biological Chemistry 274, 26523-8Google Scholar
2Quagliarini, F. et al. (2012) Atypical angiopoietin-like protein that regulates ANGPTL3. Proceedings of the National Academy of Sciences of the United States of America 109, 19751-6Google Scholar
3Tabata, M. et al. (2009) Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metabolism 10, 178-88Google Scholar
4Kadomatsu, T., Tabata, M. and Oike, Y. (2011) Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases. FEBS Journal 278, 559-64CrossRefGoogle ScholarPubMed
5Li, Q. et al. (2013) Serum Angptl2 levels are independently associated with albuminuria in type 2 diabetes. Diabetes Research & Clinical Practice 100, 385-90Google Scholar
6Usui, T. et al. (2013) Angiopoietin-like protein 2 is associated with chronic kidney disease in a general Japanese population: the Hisayama Study. Circulation Journal 77, 2311-7Google Scholar
7Odagiri, H. et al. (2014) The secreted protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin alpha5beta1, p38 MAPK, and matrix metalloproteinases. Science Signaling 7, ra7Google Scholar
8Broxmeyer, H.E. et al. (2011) Angiopoietin-like-2 and -3 act through their coiled-coil domains to enhance survival and replating capacity of human cord blood hematopoietic progenitors. Blood Cells Molecules and Diseases 48, 25-9CrossRefGoogle ScholarPubMed
9Kubota, Y. et al. (2005) Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development. Proceedings of the National Academy of Sciences of the United States of America 102, 13502-7Google Scholar
10Zheng, J. et al. (2012) Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656-60CrossRefGoogle ScholarPubMed
11Horio, E. et al. (2014) Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. Arteriosclerosis Thrombosis & Vascular Biology 34, 790-800Google Scholar
12Oike, Y. and Tabata, M. (2009) Angiopoietin-like proteins – potential therapeutic targets for metabolic syndrome and cardiovascular disease. Circulation Journal 73, 2192-7Google Scholar
13Fan, X. et al. (2014) Paired immunoglobin-like receptor B regulates platelet activation. Blood 124, 2421-30Google Scholar
14Farhat, N. et al. (2013) Angiopoietin-like 2 promotes atherogenesis in mice. Journal of American Heart Association 2, e000201CrossRefGoogle ScholarPubMed
15Toyono, T. et al. (2013) Angiopoietin-like protein 2 is a potent hemangiogenic and lymphangiogenic factor in corneal inflammation. Investigative Ophthalmology & Visual Science 54, 4278-85Google Scholar
16Richardson, M.R. et al. (2014) Angiopoietin-like protein 2 regulates endothelial colony forming cell vasculogenesis. Angiogenesis 17, 675-683Google Scholar
17Aoi, J. et al. (2011) Angiopoietin-like protein 2 is an important facilitator of inflammatory carcinogenesis and metastasis. Cancer Research 71, 7502-12Google Scholar
18Aoi, J. et al. (2014) Angiopoietin-like protein 2 accelerates carcinogenesis by activating chronic inflammation and oxidative stress. Molecular Cancer Research 12, 239-249Google Scholar
19Mederle, K. et al. (2013) The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension. Critical Care 17, R130Google Scholar
20Tazume, H. et al. (2012) Macrophage-derived angiopoietin-like protein 2 accelerates development of abdominal aortic aneurysm. Arteriosclerosis Thrombosis & Vascular Biology 32, 1400-9Google Scholar
21Tian, Z. et al. (2013) Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. Journal of Molecular & Cellular Cardiology 57, 1-12Google Scholar
22Yu, C. et al. (2013) Angiopoietin like-2 (Angptl2) knock-down limits high-fat diet-induced fat accumulation, hypercholesterolemia and prevents endothelial dysfunction in mice. Circulation 128, A14771Google Scholar
23Yu, C. et al. (2014) Lack of angiopoietin-like-2 expression limits the metabolic stress induced by a high-fat diet and maintains endothelial function in mice. Journal of American Heart Association 3, e001024Google Scholar
24Kadomatsu, T. et al. (2014) Diverse roles of ANGPTL2 in physiology and pathophysiology. Trends in Endocrinology & Metabolism 25, 245-54Google Scholar
25Oike, Y., Yasunaga, K. and Suda, T. (2004) Angiopoietin-related/angiopoietin-like proteins regulate angiogenesis. International Journal of Hematology 80, 21-8Google Scholar
26Hato, T., Tabata, M. and Oike, Y. (2008) The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends in Cardiovascular Medicine 18, 6-14Google Scholar
27Akhter, S. et al. (2013) Dynamic roles of angiopoietin-like proteins 1, 2, 3, 4, 6 and 7 in the survival and enhancement of ex vivo expansion of bone-marrow hematopoietic stem cells. Protein & Cell 4, 220-30CrossRefGoogle Scholar
28Zhang, C.C. et al. (2006) Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine 12, 240-5Google Scholar
29Deng, M. et al. (2014) A motif in LILRB2 critical for Angptl2 binding and activation. Blood 124, 924-35Google Scholar
30Kubota, Y. (2014) Unveiling Angptl2, a rising HSC expander. Blood 124, 833-4Google Scholar
31Guo, D.F. et al. (2006) Development of hypertension and kidney hypertrophy in transgenic mice overexpressing ARAP1 gene in the kidney. Hypertension 48, 453-9Google Scholar
32Guo, D.F. et al. (2003) Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane. Biochemical and Biophysical Research Communications 310, 1254-65Google Scholar
33Guo, D.F. et al. (2001) The angiotensin II type 1 receptor and receptor-associated proteins. Cell Research 11, 165-80Google Scholar
34Endo, M. et al. (2012) Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis. Cancer Research 72, 1784-94CrossRefGoogle ScholarPubMed
35Sasaki, H. et al. (2012) Angiopoietin-like protein ANGPTL2 gene expression is correlated with lymph node metastasis in lung cancer. Oncology Letters 4, 1325-1328Google Scholar
36Szarc Vel Szic, K. et al. (2014) Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells. PLoS ONE 9, e87850Google Scholar
37Teicher, B.A. (2012) Searching for molecular targets in sarcoma. Biochemical Pharmacology 84, 1-10Google Scholar
38Endo, M. et al. (2014) Serum ANGPTL2 levels reflect clinical features of breast cancer patients: implications for the pathogenesis of breast cancer metastasis. International Journal of Biological Markers 29, e239-45Google Scholar
39Gao, L. et al. (2014) ANGPTL2 promotes tumor metastasis in hepatocellular carcinoma. Journal of Gastroenterology & Hepatology (epub)Google Scholar
40Zhou, J. et al. (2014) Angiopoietin-like protein 2 negatively regulated by microRNA-25 contributes to the malignant progression of colorectal cancer. International Journal of Molecular Medicine 34, 1286-92Google Scholar
41Doi, Y. et al. (2013) Angiopoietin-like protein 2 and risk of type 2 diabetes in a general Japanese population: the Hisayama study. Diabetes Care 36, 98-100Google Scholar
42Meng, Q.X. et al. (2013) Association of serum angiopoietin-like protein 2 and epinephrine levels in metabolically healthy but obese individuals: in vitro and in vivo evidence. Experimental and Therapeutic Medicine 5, 1631-1636Google Scholar
43Muramoto, A. et al. (2011) Angiopoietin-like protein 2 sensitively responds to weight reduction induced by lifestyle intervention on overweight Japanese men. Nutrition & Diabetes 1, e20Google Scholar
44Okada, T. et al. (2010) Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis. American Journal of Pathology 176, 2309-19Google Scholar
45Ogata, A. et al. (2012) The role of angiopoietin-like protein 2 in pathogenesis of dermatomyositis. Biochemical and Biophysical Research Communications 418, 494-9Google Scholar
46Nakamura, T. et al. (2014) Angiopoietin-like protein 2 induced by mechanical stress accelerates degeneration and hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis. PLoS ONE 9, e85542Google Scholar
47Santulli, G. (2014) Angiopoietin-like proteins: a comprehensive look. Frontiers in Endocrinology (Lausanne) 5, 4Google Scholar
48Morisada, T. et al. (2006) Angiopoietins and angiopoietin-like proteins in angiogenesis. Endothelium 13, 71-9Google Scholar
49Swain, L. et al. (2014) Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions. Journal of Leukocyte Biology 96, 365-75Google Scholar
50Mitko, K. et al. (2008) Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle. Reproduction 135, 225-40CrossRefGoogle ScholarPubMed
51Haddad, R. et al. (2008) Angiogenesis gene expression in mouse uterus during the common pathway of parturition. American Journal of Obstetrics & Gynecology 198, 539, e1-8Google Scholar
52Niki, D., Katsu, K. and Yokouchi, Y. (2009) Ontogeny of angiopoietin-like protein 1, 2, 3, 4, 5, and 7 genes during chick embryonic development. Development Growth and Differentiation 51, 821-32Google Scholar
53Buga, A.M. et al. (2014) Transcriptomics of post-stroke angiogenesis in the aged brain. Frontiers in Aging Neuroscience 6, 44Google Scholar
54Lee, S. et al. (2012) Identification of genes underlying different methylation profiles in refractory anemia with excess blast and refractory cytopenia with multilineage dysplasia in myelodysplastic syndrome. Korean Journal of Hematology 47, 186-93Google Scholar
55Castrop, H. (2013) Angiotensin receptor-associated proteins: local modulators of the renin-angiotensin system. Pflugers Archiv 465, 111-9CrossRefGoogle ScholarPubMed
56Higuchi, S. et al. (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clinical Science (London) 112, 417-28Google Scholar
57Doblinger, E. et al. (2012) Angiotensin AT1 receptor-associated protein Arap1 in the kidney vasculature is suppressed by angiotensin II. American Journal of Physiology – Renal Physiology 302, F1313-24Google Scholar
58Kitazawa, M. et al. (2011) Angiopoietin-like 2, a circadian gene, improves type 2 diabetes through potentiation of insulin sensitivity in mice adipocytes. Endocrinology 152, 2558-67Google Scholar
59Kadomatsu, T. et al. (2013) A molecular clock regulates angiopoietin-like protein 2 expression. PLoS ONE 8, e57921Google Scholar
60Kikuchi, R. et al. (2008) Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. Cancer Research 68, 5067-75Google Scholar
61Kenney, S. et al. (2011) ASPS-1, a novel cell line manifesting key features of alveolar soft part sarcoma. Journal of Pediatric Hematology-Oncology 33, 360-8Google Scholar
62Stockwin, L.H. et al. (2009) Gene expression profiling of alveolar soft-part sarcoma (ASPS). BMC Cancer 9, 22Google Scholar
63Tateya, S., Kim, F. and Tamori, Y. (2013) Recent advances in obesity-induced inflammation and insulin resistance. Frontiers in Endocrinology (Lausanne) 4, 93Google Scholar
64Sun, H. et al. (2007) Enhanced expression of ANGPTL2 in the microvascular lesions of diabetic glomerulopathy. Nephron Experimental Nephrology 105, e117-23Google Scholar
65Farhat, N. et al. (2008) Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. Canadian Journal of Physiology and Pharmacology 86, 761-9Google Scholar
66Horio, E. et al. (2010) Angiopoietin-like protein 2 (angptl2) promotes coronary endothelial dysfunction and atherosclerosis. Circulation 122, Abstract 11343Google Scholar
67Horio, E. et al. (2013) Vascular tissue-derived Angptl2 accelerates atherosclerosis through increased vascular inflammation. Circulation 128, Abstract 13942Google Scholar
68Miida, T. and Hirayama, S. (2010) Impacts of angiopoietin-like proteins on lipoprotein metabolism and cardiovascular events. Current Opinion in Lipidology 21, 70-5Google Scholar
69Shimizu, I. and Walsh, K. (2013) Vascular remodeling mediated by Angptl2 produced from perivascular adipose tissue. Journal of Molecular & Cellular Cardiology 59, 176-8Google Scholar
70Dei Cas, A. and Gnudi, L. (2012) VEGF and angiopoietins in diabetic glomerulopathy: how far for a new treatment? Metabolism 61, 1666-73Google Scholar
71Kanda, A. et al. (2012) Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye. Laboratory Investigation 92, 1553-63Google Scholar
72Ambati, B. (2013) A new target for simultaneous inhibition of hem- and lymphangiogenesis. Investigative Ophthalmology & Visual Science 54, 4286Google Scholar
73Zheng, J.Y. et al. (2011) Tumor necrosis factor-alpha increases angiopoietin-like protein 2 gene expression by activating Foxo1 in 3T3-L1 adipocytes. Molecular and Cellular Endocrinology 339, 120-9Google Scholar
74Lee, H.J. et al. (2013) Angiopoietin-like protein 2, a chronic inflammatory mediator, is a new target induced by TGF-beta1 through a Smad3-dependent mechanism. Biochemical and Biophysical Research Communications 430, 981-6Google Scholar
75Jung, J.H. et al. (2010) Mel-18, a mammalian Polycomb gene, regulates angiogenic gene expression of endothelial cells. Biochemical and Biophysical Research Communications 400, 523-30Google Scholar
76Fu, Z. et al. (2013) Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochemical and Biophysical Research Communications 430, 1126-31Google Scholar
77Li, C. (2006) Genetics and regulation of angiopoietin-like proteins 3 and 4. Current Opinion in Lipidology 17, 152-6CrossRefGoogle Scholar
78Mattijssen, F. and Kersten, S. (2012) Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochimica et Biophysica Acta 1821, 782-9Google Scholar
79Savoia, C. et al. (2011) Angiotensin II and the vascular phenotype in hypertension. Expert Reviews in Molecular Medicine 13, e11CrossRefGoogle ScholarPubMed