Mette K Hagensen1, Martin Bødtker Mortensen2, Mads Kjolby3, Ninna L Stillits2, Lasse B Steffensen4, Jacob F Bentzon5. 1. Atherosclerosis Research Unit, Institute of Clinical Medicine and Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. Electronic address: mette.hagensen@clin.au.dk. 2. Atherosclerosis Research Unit, Institute of Clinical Medicine and Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. 3. Danish Diabetes Academy, Department of Biomedicine, Aarhus University, Aarhus, Denmark. 4. Atherosclerosis Research Unit, Institute of Clinical Medicine and Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. 5. Atherosclerosis Research Unit, Institute of Clinical Medicine and Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Abstract
BACKGROUND AND AIMS: Individuals with type 1 diabetes mellitus are at high risk of developing atherosclerotic cardiovascular disease, but the underlying mechanisms by which type 1 diabetes accelerates atherosclerosis remain unknown. Increased retention of low-density lipoprotein (LDL) in atherosclerosis-prone sites of the diabetic vascular wall has been suggested, but direct evidence is lacking. In the present study, we investigated whether retention of LDL is increased in atherosclerotic-prone areas using a murine model of type 1 diabetes. METHODS: Fluorescently-labeled human LDL from healthy non-diabetic individuals was injected into diabetic Ins2Akita mice and non-diabetic, wild-type littermates. The amount of retained LDL after 24 h was quantified by fluorescence microscopy of cryosections and by scans of en face preparations. Vascular gene expression in the inner curvature of the aortic arch was analyzed by microarray and quantitative polymerase chain reaction. RESULTS: LDL retention was readily detected in atherosclerosis-prone areas of the aortic arch being located in both intimal and medial layers. Quantitative microscopy revealed 8.1-fold more retained LDL in type 1 diabetic mice compared to wild-type mice. These findings were confirmed in independent experiments using near-infrared scanning of en face preparations of the aorta. Diabetic status did not affect arterial expression of genes known to be involved in LDL retention. CONCLUSIONS: Type 1 diabetes increases the ability of the vascular wall to retain LDL in mice. These changes could contribute to the increased atherosclerotic burden seen in type 1 diabetic patients.
BACKGROUND AND AIMS: Individuals with type 1 diabetes mellitus are at high risk of developing atherosclerotic cardiovascular disease, but the underlying mechanisms by which type 1 diabetes accelerates atherosclerosis remain unknown. Increased retention of low-density lipoprotein (LDL) in atherosclerosis-prone sites of the diabetic vascular wall has been suggested, but direct evidence is lacking. In the present study, we investigated whether retention of LDL is increased in atherosclerotic-prone areas using a murine model of type 1 diabetes. METHODS: Fluorescently-labeled human LDL from healthy non-diabetic individuals was injected into diabetic Ins2Akita mice and non-diabetic, wild-type littermates. The amount of retained LDL after 24 h was quantified by fluorescence microscopy of cryosections and by scans of en face preparations. Vascular gene expression in the inner curvature of the aortic arch was analyzed by microarray and quantitative polymerase chain reaction. RESULTS: LDL retention was readily detected in atherosclerosis-prone areas of the aortic arch being located in both intimal and medial layers. Quantitative microscopy revealed 8.1-fold more retained LDL in type 1 diabeticmice compared to wild-type mice. These findings were confirmed in independent experiments using near-infrared scanning of en face preparations of the aorta. Diabetic status did not affect arterial expression of genes known to be involved in LDL retention. CONCLUSIONS: Type 1 diabetes increases the ability of the vascular wall to retain LDL in mice. These changes could contribute to the increased atherosclerotic burden seen in type 1 diabeticpatients.