Angiopoietin-like proteins as therapeutic targets for cardiovascular disease: focus on lipid disorders

ABSTRACT

Introduction: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the ‘ANGPT L3-4-8 triad’), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.

Areas covered: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.

Expert opinion: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans.

KEYWORDS:

• Angiopoietin
• ANGPTL
• ANGPTL3-4-8 triad
• cardiovascular disease
• cholesterol
• diabetes mellitus
• evinacumab
• LPL
• metabolic syndrome obesity
• PCSK9
• REGN3776
• triglycerides

Article Highlights

• ANGPTL3, ANGPTL4, and ANGPTL8 (the 3-4-8 triad) are largely studied for their crucial role as negative regulators of LPL activity.

• ANGPTL8 functions as a metabolic switch by forming complexes with ANGPTL3 or ANGPTL4.

• Subjects with LoF mutations in ANGPTL3 have reduced plasma level of TGs, VLDL, and LDL-C.

• The missense E40K variant in ANGPTL4 protein associates with decreased levels of TGs and increased levels of HDL-C.

• Monoclonal antibodies targeting ANGPTL3, ANGPTL4, and ANGPTL8 are effective in reducing TG levels

• Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an early stage in development and hence further investigations are necessary for eventual use in humans.

This box summarizes key points contained in the article.

Reviewer disclosures

One reviewer has an affiliation with the biotech company Lipigon Pharmaceuticals. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The Santulli's lab is supported by the NIH (R01-DK123259, R01-HL146691, R00-DK107895, P30-DK020541, R01-DK033823 to G.S.).