Angiopoietin-Like Proteins Potential Therapeutic Targets for Metabolic Syndrome and Cardiovascular Disease

Abstract

Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed and developing countries, are an exploding medical and social problem. These conditions are associated with increased risk of cardiovascular disease (CVD), the leading cause of death. Thus, it is necessary to understand the molecular basis underlying MetS and develop effective preventive and therapeutic approaches against CVD. To date, 7 angiopoietin-like proteins (Angptls) that are structurally similar to angiopoietins have been identified. However, none binds to the angiopoietin receptor, Tie2, or to the closely related Tie1 receptor, suggesting that these ligands function differently from angiopoietins. Some Angptls potently regulate angiogenesis, similar to angiopoietins, whereas others have pleiotropic activity other than angiogenesis and function in lipid and energy metabolism. In this review, we focus on the roles of Angptl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD, and discuss the potential for Angptl2 and Angptl6/AGF to function as molecular targets for the prevention and treatment of both conditions. (Circ J 2009; 73: 2192 -2197

Angiopoietin-like protein 2 sensitively responds to weight reduction induced by lifestyle intervention on overweight Japanese men

“…20, 21, 22 We found that Angptl2 levels tended to decrease immediately in subjects showing 2% or more weight reduction and continued until 3 months after the intervention. Angptl2 gradually decreased with increased weight reduction, and those decreases in the 6% or more weight reduction group were significant compared with the unchanged control group, indicative of an early effect of weight reduction on improved metabolism.…”

“…20, 21, 22 We observed accumulation of fat in the liver and skeletal muscle was mild in Angptl2 knockout mice compared with wild-type mice, and Angptl2 deletion ameliorated adipose tissue inflammation. 20 We also observed significant decreases in circulating Angptl2 concentrations in obese diabetic men following treatment with the PPARγ agonist pioglitazone, and the percent decrease in Angptl2 levels was positively correlated with the percent decreases in visceral fat area.…”

“…These findings suggest that visceral fat is a likely primary source of circulating Angptl2 and that levels of that factor are significantly correlated with systemic insulin resistance and inflammation. 20, 21, 22 …”

Human adipose dynamics and metabolic health

“…178 Angiopoietins and their receptors, as well as the apelin-APJ signaling pathway, can also be promising targets for anti-angiogenesis of WAT. 179, 180 Established vasculature of WAT could be targeted as well since data from animal studies showed that a cytotoxic peptide fused to the ligand of prohibitin, a receptor specifically located to WAT endothelium, resulted in rapid obesity reversal upon daily subcutaneous injection; 181 similar results were obtained from a rat model of obesity. 182 Future translational studies will be necessary to validate this approach.…”

New Therapeutic Targets for Intraocular Pressure Lowering

“…Angiopoietin-like (ANGPTL) molecules are a family of glycoproteins which resemble angiopoietins structurally [82] but fail to bind the angiopoietin receptors Tie1 and Tie2 [83–85]. Despite these, some of the members in this family are potent regulators of angiogenesis [86, 87] and function as mediators in the induction of inflammation and regulation of lipid and glucose metabolism [88–90].…”