Abstract
During atherogenesis, low density lipoprotein (LDL) particles in the arterial intima become modified and fuse to form extracellular lipid droplets. Proteolytic modification of apolipoprotein (apo) B-100 may be one mechanism of droplet formation from LDL. Here we studied whether the newly described acid protease cathepsin F can generate LDL-derived lipid droplets in vitro. Treatment of LDL particles with human recombinant cathepsin F led to extensive degradation of apoB-100, which, as determined by rate zonal flotation, electron microscopy, and NMR spectroscopy, triggered both aggregation and fusion of the LDL particles. Two other acid cysteine proteases, cathepsins S and K, which have been shown to be present in the arterial intima, were also capable of degrading apoB-100, albeit less efficiently. Cathepsin F treatment resulted also in enhanced retention of LDL to human arterial proteoglycans in vitro. Cultured monocyte-derived macrophages were found to secrete active cathepsin F. In addition, similarly with cathepsins S and K, cathepsin F was found to be localized mainly within the macrophage-rich areas of the human coronary atherosclerotic plaques. These results suggest that proteolytic modification of LDL by cathepsin F may be one mechanism leading to the extracellular accumulation of LDL-derived lipid droplets within the proteoglycan-rich extracellular matrix of the arterial intima during atherogenesis.
Highlights
During atherogenesis, lipid droplets accumulate extracellularly within the inner layer of the arterial wall, the intima
With cathepsins S and K, cathepsin F was found to be localized mainly within the macrophage-rich areas of the human coronary atherosclerotic plaques. These results suggest that proteolytic modification of low density lipoprotein (LDL) by cathepsin F may be one mechanism leading to the extracellular accumulation of LDL-derived lipid droplets within the proteoglycan-rich extracellular matrix of the arterial intima during atherogenesis
There is evidence that LDL particles become proteolytically modified in the arterial intima, but it appears that only a few of the proteases that are known to be present in the arterial intima are able to degrade apoB-100 extensively enough to trigger particle fusion [2]
Summary
Lipid droplets accumulate extracellularly within the inner layer of the arterial wall, the intima. The apoB-100 in the LDL particles isolated from the human atherosclerotic arterial intima is fragmented to variable degrees (10 –15). Proteolysis of apoB-100 in vitro has been shown to induce fusion of LDL particles into lipid droplets that resemble those found in atherosclerotic lesions (18 –21).
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