Mette K Hagensen1, Martin B Mortensen2, Mads Kjolby3, Johan Palmfeldt4, Jacob F Bentzon5, Soeren Gregersen6. 1. Department of Clinical Medicine, Department of Cardiology, Aarhus University, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. Electronic address: mette.hagensen@clin.au.dk. 2. Department of Clinical Medicine, Department of Cardiology, Aarhus University, Aarhus University Hospital, Aarhus, Denmark. 3. Department of Biomedicine, Department of Cardiology, Danish Diabetes Academy, Aarhus University, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Denmark. 5. Department of Clinical Medicine, Department of Cardiology, Aarhus University, Aarhus University Hospital, Aarhus, Denmark; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. 6. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
Abstract
BACKGROUND AND AIMS: Type 1 diabetes accelerates the development of atherosclerotic cardiovascular diseases. Retention of low-density lipoprotein (LDL) in the arterial wall is a causal step in atherogenesis, but it is unknown whether diabetes alters the propensity of LDL for retention. The present study investigated whether LDL from type 1 diabetic and healthy non-diabetic subjects differed in their ability to bind to the arterial wall in a type 1 diabetic mouse model. METHODS: Fluorescently-labeled LDL obtained from type 1 diabetic patients or healthy controls was injected into mice with type 1 diabetes. The amount of retained LDL in the atherosclerosis-prone inner curvature of the aortic arch was quantified by fluorescence microscopy. Healthy control LDL was in vitro glycated, analyzed for protein glycation by LC-MS/MS, and tested for retention propensity. RESULTS: Retention of LDL from type 1 diabetic patients was 4.35-fold higher compared to LDL from nondiabetic subjects. Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the concentration of the atherogenic small dense LDL between type 1 diabetic and non-diabetic subjects. In vitro glycation of LDL from a non-diabetic subject increased retention compared to non-glycated LDL. LC-MS/MS revealed four new glycated spots in the protein sequence of ApoB of in vitro glycated LDL. CONCLUSIONS: LDL from type 1 diabetic patients showed increased retention at atherosclerosis-prone sites in the arterial wall of diabetic mice. Glycation of LDL is one modification that may increase retention, but other, yet unknown, mechanisms are also likely to contribute.
BACKGROUND AND AIMS: Type 1 diabetes accelerates the development of atherosclerotic cardiovascular diseases. Retention of low-density lipoprotein (LDL) in the arterial wall is a causal step in atherogenesis, but it is unknown whether diabetes alters the propensity of LDL for retention. The present study investigated whether LDL from type 1 diabetic and healthy non-diabetic subjects differed in their ability to bind to the arterial wall in a type 1 diabeticmouse model. METHODS: Fluorescently-labeled LDL obtained from type 1 diabeticpatients or healthy controls was injected into mice with type 1 diabetes. The amount of retained LDL in the atherosclerosis-prone inner curvature of the aortic arch was quantified by fluorescence microscopy. Healthy control LDL was in vitro glycated, analyzed for protein glycation by LC-MS/MS, and tested for retention propensity. RESULTS: Retention of LDL from type 1 diabeticpatients was 4.35-fold higher compared to LDL from nondiabetic subjects. Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the concentration of the atherogenic small dense LDL between type 1 diabetic and non-diabetic subjects. In vitro glycation of LDL from a non-diabetic subject increased retention compared to non-glycated LDL. LC-MS/MS revealed four new glycated spots in the protein sequence of ApoB of in vitro glycated LDL. CONCLUSIONS: LDL from type 1 diabeticpatients showed increased retention at atherosclerosis-prone sites in the arterial wall of diabeticmice. Glycation of LDL is one modification that may increase retention, but other, yet unknown, mechanisms are also likely to contribute.
Authors: Anastasia Poznyak; Andrey V Grechko; Paolo Poggio; Veronika A Myasoedova; Valentina Alfieri; Alexander N Orekhov Journal: Int J Mol Sci Date: 2020-03-06 Impact factor: 5.923