Abstract
The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand-RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE(-/-)) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE(-/-) mice that were AT1R-deficient (ApoE(-/-)AT1aR(-/-)) were also investigated. In diabetic ApoE(-/-) mice, AT1R was found to increase within 1 week of diabetes induction, before ligand-RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand-RAGE expression and inflammatory changes. In contrast, upregulation of the ligand-RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE(-/-) mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand-RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand-RAGE signals.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Animals
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Apolipoproteins E / genetics
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Blood Pressure / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Coronary Artery Disease / genetics*
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Coronary Artery Disease / metabolism
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Coronary Artery Disease / pathology
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Coronary Artery Disease / physiopathology
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Diabetes Mellitus, Experimental / genetics*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / physiopathology
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Diabetic Angiopathies / genetics*
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Diabetic Angiopathies / metabolism
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Diabetic Angiopathies / pathology
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Diabetic Angiopathies / physiopathology
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Glycation End Products, Advanced / metabolism*
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Rats
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / genetics*
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Renin-Angiotensin System / drug effects
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Renin-Angiotensin System / physiology
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Signal Transduction / genetics
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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Agtrap protein, mouse
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Angiotensin II Type 1 Receptor Blockers
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Apolipoproteins E
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Glycation End Products, Advanced
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic