title: Lipoprotein binding to anionic biopolyelectrolytes and the effect of glucose on nanoplaque formation in arteriosclerosis and Alzheimer's disease.
abstract: Arteriosclerosis with its clinical sequelae (cardiac infarction, stroke, peripheral arterial occlusive disease) and vascular/Alzheimer dementia not only result in far more than half of all deaths but also represent dramatic economic problems. The reason is, among others, that diabetes mellitus is an independent risk factor for both disorders, and the number of diabetics strongly increases worldwide. More than one-half of infants in the first 6months of life have already small collections of macrophages and macrophages filled with lipid droplets in susceptible segments of the coronary arteries. On the other hand, the authors of the Bogalusa Heart Study found a strong increase in the prevalence of obesity in childhood that is paralleled by an increase in blood pressure, blood lipid concentration, and type 2 diabetes mellitus. Thus, there is a clear linkage between arteriosclerosis/Alzheimer's disease on the one hand and diabetes mellitus on the other hand. Furthermore, it has been demonstrated that distinct apoE isoforms on the blood lipids further both arteriosclerotic and Alzheimer nanoplaque formation and therefore impair flow-mediated vascular reactivity as well. Nanoplaque build-up seems to be the starting point for arteriosclerosis and Alzheimer's disease in their later full clinical manifestation. In earlier work, we could portray the anionic biopolyelectrolytes syndecan/perlecan as blood flow sensors and lipoprotein receptors in cell membrane and vascular matrix. We described extensively molecular composition, conformation, form and function of the macromolecule heparan sulfate proteoglycan (HS-PG). In two supplementary experimental settings (ellipsometry, myography), we utilized isolated HS-PG for in vitro nanoplaque investigations and isolated human coronary artery segments for in vivo tension measurements. With the ellipsometry-based approach, we were successful in establishing a direct connection on a molecular level between diabetes mellitus on the one side and arteriosclerosis/Alzheimer's disease on the other side. Application of glucose at a concentration representative for diabetics and leading to glycation of proteins and lipids, entailed a significant increase in arteriosclerotic and Alzheimer nanoplaque formation. IDLapoE4/E4 was by far superior to IDLapoE3/E3 in plaque build-up, both in diabetic and non-diabetic patients. Recording vascular tension of flow-dependent reactivity in blood substitute solution and under application of different IDLapoE isoforms showed an impaired vasorelaxation for pooled IDL and IDLapoE4/E4, thus confirming the ellipsometric investigations. Incubation in IDLapoE0/E0 (apoE "knockout man"), however, resulted in a massive flow-mediated contraction, also complemented by strongly aggregated nanoplaques. In contrast, HDL was shown to present a powerful protection against nanoplaque formation on principle, both in the in vitro model and the in vivo scenario on the endothelial cell membrane. The competitive interplay with LDL is highlighted through the flow experiment, where flow-mediated, HDL-induced vasodilatation remains untouched by additional incubation with LDL. This is due to the four times higher affinity for the proteoglycan receptor of HDL as compared to LDL. Taken together, the studies demonstrate that while simplistic, the ellipsometry approach and the endothelial-mimicking proteoglycan-modified surfaces provide information on the initial steps of lipoprotein-related plaque formation, which correlates with findings on endothelial cells and blood vessels, and afford insight into the role of lipoprotein deposition and exchange phenomena at the onset of these pathophysiologies.
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany; University of Uppsala Biomedical Center, 751 23 Uppsala, Sweden; St. George's University School of Arts & Sciences, True Blue, Grenada. Electronic address: guenter.siegel@charite.de.
authors.forename: G
authors.initials: G
authors.lastname: Siegel
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: F H M E
authors.initials: FHME
authors.lastname: Mockenhaupt
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Behnke
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany; Federal Institute for Materials Research and Testing (BAM), 12489 Berlin, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Ermilov
authors.affiliation: University Clinic Freiburg, 79106 Freiburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Winkler
authors.affiliation: Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: A R
authors.initials: AR
authors.lastname: Pries
authors.affiliation: University of Uppsala Biomedical Center, 751 23 Uppsala, Sweden; Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Malmsten
authors.affiliation: German Heart Institute Berlin, 13353 Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hetzer
authors.affiliation: St. George's University School of Arts & Sciences, True Blue, Grenada; Charité - University Clinic Berlin, 10117 Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Saunders
authors.affiliation: University of Lund, 221 00 Lund, Sweden; University of Coimbra, 3004-535 Coimbra, Portugal; Nanyang Technological University School of Materials Science & Engineering, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Lindman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D002118:Calcium; D003924:Diabetes Mellitus, Type 2; D005947:Glucose / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008074:Lipoproteins; D005947:Glucose; D002118:Calcium
keywords: Diabetes mellitus and Alzheimer's disease; Glucose and nanoplaque formation; HDL protection; HS-PG flow sensor and lipoprotein receptor; IDLapoE3/E3 and IDLapoE4/E4 isoforms; β-amyloid (1–42)