Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases

Despite the best pharmacological tools available, cardiovascular diseases (CVD) remain a major cause of morbidity and mortality in developed countries. After two decades of research, new therapeutic targets such as angiopoietin-like (ANGPTL) proteins are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathological functions: they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs, particularly the triad ANGPTL3, 4 and 8, have an established role in lipid metabolism, through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTLs expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders, including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the present review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTLs family in the cardiovascular system, their contribution to CVD and the therapeutic potential of manipulating some of them.