Binding of human low-density lipoproteins to type-I collagen is synergistic with the pro-atherogenic lipoprotein remodeling.

Low-density lipoprotein (LDL) entrapment in the extracellular matrix of the arterial intima is an established early trigger of atherosclerosis. Though much is known about LDL binding to arterial proteoglycans, the binding to other matrix components remains underexplored. This study focuses on LDL interactions with type-I collagen (Col-I), a major extracellular matrix protein found in atherosclerotic lesions. Human normolipidemic LDL, which has been oxidized or lipolyzed in vitro, and naturally occurring plasma LDL subclasses differing in size and charge are explored, along with LDL from patients with type-2 diabetes or obesity before and after treatment. To understand how these lipoproteins interact with Col-I, we quantify their binding to collagen-coated microwell plates using enzyme-linked immunosorbent assay. The mechanistic underpinnings are probed by a multipronged approach using the methods of chromatography, spectroscopy, microscopy and others. The results reveal that intact LDL binds Col-I in a cooperative dose-dependent manner. The binding is synergistic with pro-atherogenic LDL modifications including aggregation, oxidation and lipolysis. The pro-atherogenic subclasses of small dense LDL and electronegative LDL show enhanced Col-I binding; conversely, Col-I binding induces LDL remodeling to generate smaller and more electronegative particles. This synergy suggests a potential causal role of LDL-Col-I interactions in atherogenesis. Moreover, our results suggest that LDL binding to Col-I provides a biomarker and a sensitive treatment readout for the risk of atherosclerosis in patients with metabolic diseases such as diabetes and obesity.