Angiopoietin-2 (Ang-2; also ANGPT2) is a secreted glycoprotein that plays a complex role in angiogenesis and inflammation. Both Ang-2 and the related Angiopoietin-1 (Ang-1) are ligands for the receptor tyrosine kinase Tie-2. While Ang-1 is a potent Tie 2 agonist, Ang-2 may act as either a Tie-2 antagonist or agonist, depending upon its state of multimerization. The higher the order of oligomer, the more effective Ang-2 becomes as a Tie-2 agonist. The short isoform appears to block the binding of either Ang-1 or full-length Ang-2 to Tie-2. Ang-2 functions as a pro-angiogenic factor, although it can also induce EC death and vessel regression. Upon its release from quiescent EC, it regulates vascular remodeling by promoting EC survival, proliferation, and migration and destabilizing the interaction between EC and perivascular cells. In addition, ANG-2 is strongly expressed in the vasculature of many tumors and it has been suggested that ANG-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated Angiogenesis and tumor progression.
Angiotensin-Converting Enzyme 2 (ACE-2) is an integral membrane protein and a zinc metalloprotease of the ACE family, the ACE family includes somatic and germinal ACE. ACE-2 cleaves angiotensins I and II as a carboxypeptidase, ACE-2 converts angiotensin I to angiotensin 1-9, and angiotensin II to angiotensin 1-7. ACE-2 is also able to hydrolyze apelin-13 and dynorphin-13 with high efficiency. ACE-2 can be high expressed in testis, kidney and heart, in colon, small intestine and ovary at moderate levels. Captopril and lisinopril as the classical ACE inhibitor don’t inhibit ACE-2 activity. ACE-2 may play an important role in regulating the heart function.
ANGPTL3 is a secreted glycoprotein that is structurally related to the angiopoietins. Mature mouse ANGPTL3 contains an N-terminal coiled coil domain and a C-terminal fibrinogen-like domain. ANGPTL3 is expressed in the liver from early in development through adulthood. Full length ANGPTL3 circulates in the plasma as do the proteolytically separated N-and C-terminal fragments containing the coiled-coil domain and fibrinogen-like domains, respectively. ANGPTL3 is found as 70 kDa, 50 kDa, and 32 kDa species and can form weakly associated noncovalent multimers in vitro. ANGPTL3 directly inhibits lipoprotein lipase (LPL), an enzyme responsible for hydrolyzing circulating triglycerides. This activity requires a putative heparin binding motif that is N-terminal to the coiled coil domain. Proteolytic removal of the fibrinogen-like domain from the N-terminal fragment serves to activate ANGPTL3 and increase its ability to inhibit LPL in vitro and function in vivo. ANGPTL3 promotes an increase in circulating triglyceride levels without altering VLDL or HDL secretion or uptake. ANGPTL3 knockout mice are hypolipidemic and have elevated LPL activity. ANGPTL3 expression in vivo is up regulated by LXR agonists and down regulated by insulin, leptin, and TR beta agonists. Dysregulated ANGPTL3 expression and elevated plasma triglyceride levels are characteristic of some strains of obese and diabetic mice. ANGPTL3 does not bind Tie-1 or Tie-2 but its fibrinogen-like domain interacts with integrin alpha V beta 3 to induce endothelial cell adhesion, migration, and neovascularization. ANGPTL3, secreted by fetal liver cells, also promotes the expansion of hematopoietic stem cells. Mature mouse ANGPTL3 shares 22%-30% amino acid (aa) sequence identity with ANGPTL1, 2, 4, 6, and 7. It shares 77% aa sequence identity with human ANGPTL3.
Angiopoietin-likeProtein 3 (ANGPTL3) is a secreted glycoprotein that is structurally related to the angiopoietins. Mature mouse ANGPTL3 contains an N-terminalcoiled coil domain and a C-terminalfibrinogen-likedomain. Within the Nterminalfragment, mouse ANGPTL3 shares 83% and 92% aa sequence identity with human and rat ANGPTL3, respectively. ANGPTL3 is expressed in the liver from early in development through adulthood. ANGPTL3 directly inhibits lipoprotein lipase (LPL) and endothelial lipase (EL), enzymesresponsible for hydrolyzing circulating triglycerides and HDL phospholipids. This activity requires a putative heparin-bindingmotif which is N-terminalto thecoiled coil domain. Proteolytic removal of the fibrinogen-likedomain from the N-terminalfragment serves to activate ANGPTL3 and increase its ability toinhibit LPL in vitro and function in vivo. ANGPTL3 promotes an increase in circulating triglyceride levels without altering VLDL or HDL secretion oruptake. ANGPTL3 expression in vivo is up-regulatedby LXR agonists anddown-regulatedby insulin, leptin, and agonists of TRβ or PPARβ. ANGPTL3, secreted by fetal liver cells, also promotes the expansion of hematopoietic stem cells.
ANGPTL4, also known as ANGPTL2, is a protein with hypoxia-induced expression in endothelial cells. It contains 1 fibrinogen C-terminal domain and is expressed at high levels in the placenta, heart, liver, muscle, pancreas and lung but expressed poorly in the brain and kidney. ANGPTL4 inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage. It may act as a regulator of angiogenesis and modulate tumorigenesis. It inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage. It may also exert a protective function on endothelial cells through an endocrine action. ANGPTL4 is directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. In response to hypoxia, the unprocessed form of the protein accumulates in the subendothelial extracellular matrix (ECM). The matrix-associated and immobilized unprocessed form limits the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibits their adhesion. It also decreases motility of endothelial cells and inhibits the sprouting and tube formation.
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