ANGPTL8 is a negative regulator in pathological cardiac hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Endocrinology

Background:

• Pathological cardiac hypertrophy is a key risk factor for heart failure, yet its underlying mechanisms are not fully understood.
• Identifying novel therapeutic targets for cardiac hypertrophy is crucial for managing heart failure.

Purpose of the Study:

• To investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy.
• To elucidate the molecular mechanisms by which ANGPTL8 influences cardiac hypertrophy.

Main Methods:

• Serum ANGPTL8 levels were measured in hypertensive patients and in mouse models of cardiac hypertrophy (Ang II and TAC).
• ANGPTL8 function was assessed in vivo using ANGPTL8-deficient mice and in vitro using neonatal rat cardiomyocytes and H9c2 cells treated with recombinant ANGPTL8.
• Molecular mechanisms were investigated through analysis of Akt and GSK-3β activation, and ANGPTL8 interaction with LILRB3 (PIRB) was confirmed via RNA-seq and immunoprecipitation-mass screening.

Main Results:

• Serum ANGPTL8 levels were elevated in patients and mice with cardiac hypertrophy.
• ANGPTL8 deficiency exacerbated cardiac hypertrophy, fibrosis, and dysfunction in mice.
• Recombinant ANGPTL8 and overexpression mitigated Ang II-induced cardiomyocyte enlargement by inhibiting Akt/GSK-3β activation.
• ANGPTL8 directly binds to LILRB3 (PIRB), and blocking this interaction abrogated ANGPTL8's antihypertrophic effects.

Conclusions:

• ANGPTL8 is a novel negative regulator of pathological cardiac hypertrophy.
• The antihypertrophic effects of ANGPTL8 are mediated through its interaction with LILRB3 (PIRB) and subsequent inhibition of Akt/GSK3β signaling.
• ANGPTL8 represents a potential therapeutic target for cardiac hypertrophy and heart failure, possibly in combination with AT1 blockers.