Intimal hyperplasia induced by vascular intervention causes lipoprotein retention and accelerated atherosclerosis

Abstract

Accelerated atherosclerosis diminishes the long term patency of vascular interventions, such as percutaneous coronary intervention and implantation of saphenous vein grafts. However, the cause of this accelerated atherosclerosis is unclear. In this study, we tested the hypothesis that intimal hyperplasia formed following vascular intervention promotes retention of atherogenic lipoproteins. Intimal hyperplasia was surgically induced in the mouse common carotid artery. The surgery was combined with different mouse models of hypercholesterolemia to obtain different cholesterol levels and to control the onsets of hypercholesterolemia. Three weeks after surgery, samples were immunostained for apoB lipoproteins, smooth muscle cells and leukocytes. Already at mild hypercholesterolemia (193 mg/dL), pronounced apoB lipoprotein retention was found in the extracellular matrix in both intimal hyperplasia and the injured underlying media. In contrast, minimal retention was detected in the uninjured proximal region of the same vessel, or in vessels from mice with normal cholesterol levels (81 mg/dL). Induction of aggravated hypercholesterolemia 3 weeks after surgery, when a mature intimal hyperplasia had been formed, caused a very rapid development of atherosclerotic lesions. Mechanistically, we show that lipoprotein retention was almost exclusively dependent on electrostatic interactions to proteoglycan glycosaminoglycans, and the lipoprotein retention to intimal hyperplasia could be inhibited in vivo using glycosaminoglycan‐binding antibodies. Thus, formation of intimal hyperplasia following vascular intervention makes the vessel wall highly susceptible for lipoprotein retention and accelerated atherosclerosis. The increased lipoprotein retention in intimal hyperplasia can be targeted by blocking the interaction between apoB lipoproteins and glycosaminoglycans in the extracellular matrix.

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

“…It can also be mentioned that there is an alternative approach of targeting GAG chain biosynthesis which is to use GAG-directed antibodies which block the ionic interaction between GAG chains and ApoB100; the veracity of this approach has recently been demonstrated in a mouse model of intimal hyperplasia where the accelerated atherosclerosis was shown to be due to lipoprotein binding to modified proteoglycans and the interaction and hence the atherosclerosis could be blocked by GAG directed antibodies (Kijani et al, 2017). It follows in this area that an "antiproteoglycan" or more specially an "anti-GAG" agent would work in therapeutic tandem with a HMG-CoA reductase inhibitor such as a statin.…”

Low density lipoprotein-induced lipid accumulation is a key phenomenon of atherogenesis at the arterial cell level

“…In contrast to the outdated concepts of the total level of circulating LDL as a cause for the formation of atherosclerotic lesion, it seems more reasonable the idea that the key initiating event in atherogenesis is the retention, or trapping, of LDL within the arterial wall [62,63] . The paradigm of the key role of LDL and foam cells in atherogenesis gave rise to the concept of cellular cholesterol retention [64,65] .…”

ApoB-100 Lipoprotein Complex Formation with Intima Proteoglycans as a Cause of Atherosclerosis and Its Possible Ex Vivo Evaluation as a Disease Biomarker

“…There are other conditions that can cause matrix production with an increased capacity to retain apoB-100 lipoproteins mediated by PGs. Recently, Kijani et al found that vascular interventions in the common carotid of mice, resulting in intimal hyperplasia, induced deposition of apoB-100 lipoproteins and rapid atherosclerosis [ 44 ]. Further confirmation of the importance of the extracellular matrix proteoglycan structure on retention of apoB lipoproteins in atherogenesis was recently reported by Bach Steffensen and collaborators [ 45 ].…”