Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells

Area of Science:

• Biochemistry
• Cell Biology
• Cardiovascular Research

Background:

• Atherosclerosis involves cholesterol accumulation in macrophages.
• Defective cholesterol removal by high-density lipoproteins (HDL) contributes to this accumulation.
• The role of specific cathepsins in HDL function and cholesterol efflux is not fully understood.

Purpose of the Study:

• To investigate the proteolytic effects of cathepsins F, S, and K on HDL and apoA-I.
• To determine the consequence of cathepsin activity on cholesterol efflux from macrophages.
• To elucidate the potential role of cathepsins in foam cell formation in atherosclerosis.

Main Methods:

• In vitro incubation of HDL(3) and lipid-free apoA-I with cathepsins F, S, and K.
• Measurement of prebeta-HDL levels.
• Assessment of cholesterol efflux from cholesterol-loaded mouse peritoneal macrophages.

Main Results:

• Cathepsin F or S rapidly degraded HDL(3), reducing cholesterol efflux by 50% within 1 minute.
• Cathepsins F or K partially degraded apoA-I, diminishing its cholesterol efflux-inducing capacity.
• Cathepsin S completely degraded apoA-I, abolishing its cholesterol acceptor function.

Conclusions:

• Cathepsin-secreting cells rapidly deplete lipid-poor HDL (prebeta-HDL) and lipid-free apoA-I.
• Inhibition of cellular cholesterol efflux by cathepsins promotes foam cell formation and maintenance in atherosclerotic lesions.