Abstract
BackgroundAtherosclerosis is an inflammatory process involving activation of monocytes recruited by various chemoattractant factors, among which lipoprotein(a) and its specific apolipoprotein apo(a). Lp(a) contains a specific apolipoprotein apo(a) which size is determined by a variable number of repeats of a specific structural domain, the kringle IV type 2 (IV-2). Lp(a) plasma concentration and apo(a) size is inversely correlated, and smaller apo(a) are major risk factors for coronary heart disease.Design and methodsThe aim of this study was to evaluate the effect of recombinant apo(a) isoforms (containing 10, 18 or 34 kringles) on monocytes interacting with type I collagen.ResultsApo(a) isoforms stimulated reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) production by monocytes, and not modified monocytes adhesion on type I collagen. This effect was specific of apo(a) since no effect was observed in the presence of plasminogen and was inversely related to apo(a) size. The lysine analogue 6-aminohexanoic acid which blocks the lysine binding sites (LBS), and carboxypeptidase B (CpB) which cleaves carboxy-terminal lysine residues, abolished apo(a)-induced ROS and MMP-9 production, highlighting an effect mediated by apo(a) lysing-binding sites.ConclusionsThese results indicate that activation of collagen-primed monocytes stimulated with apo(a) is a Kringle number-dependent effect and reinforce the hypothesis of a role for small size apo(a) isoforms in atherothrombosis.
Highlights
A characteristic feature in the development of atherosclerotic lesions is the accumulation of foam cells, i.e. monocyte-derived macrophages that store cholesteryl esters, resulting from low-density lipoprotein (LDL) uptake [1]
The lysine analogue 6-aminohexanoic acid which blocks the lysine binding sites (LBS), and carboxypeptidase B (CpB) which cleaves carboxy-terminal lysine residues, abolished apo(a)-induced reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) production, highlighting an effect mediated by apo(a) lysing-binding sites
These results indicate that activation of collagen-primed monocytes stimulated with apo(a) is a Kringle number-dependent effect and reinforce the hypothesis of a role for small size apo(a) isoforms in atherothrombosis
Summary
A characteristic feature in the development of atherosclerotic lesions is the accumulation of foam cells, i.e. monocyte-derived macrophages that store cholesteryl esters, resulting from low-density lipoprotein (LDL) uptake [1]. Clinical evidences suggest that apo(a) may be involved in pathogenic events, since an inverse correlation has been established between apo(a) size and the increased occurrence of coronary artery lesions [4, 10, 11]. Besides it has been shown that low molecular weight apo (a) isoforms were associated with a high risk of major adverse cardiovascular events within 15 years after coronary artery bypass [12]. Described in a Danish population a high risk of mortality associated with high concentrations of lipoprotein(a), related to low KIV-2 number of repeats rather than to high cholesterol content [13]. Atherosclerosis is an inflammatory process involving activation of monocytes recruited by various chemoattractant factors, among which lipoprotein(a) and its specific apolipoprotein apo(a). Lp(a) plasma concentration and apo(a) size is inversely correlated, and smaller apo(a) are major risk factors for coronary heart disease
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