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Increased Arterial Exposure to Remnant Lipoproteins Leads to Enhanced Deposition of Cholesterol and Binding to Glycated Extracellular Matrix Proteoglycans
Abstracts / Atherosclerosis Supplements 11 (2010) 65–83
CLA (p < 0.05) or the VA + CLA diet (p < 0.001) relative to controls. Conclusion: Combination of VA and CLA results in a synergistic improvement of fasting and post-prandial lipid metabolism in the JCR:LA-cp rat. Combination of both VA and CLA may in part contribute to the hypolipidemic benefits on circulating dyslipidemia and hepatic steatosis in this rat model. doi:10.1016/j.atherosclerosissup.2010.04.029 Abstract:24 Increased Arterial Exposure to Remnant Lipoproteins Leads to Enhanced Deposition of Cholesterol and Binding to Glycated Extracellular Matrix Proteoglycans R. Mangat 1 , Y. Wang 1 , R.R. Uwiera 1 , D.F. Vine 1 , J.C.L. Mamo 2 , S.D. Proctor 1 1 Alberta
Institute for Human Nutrition, University of Alberta, Edmonton, Canada 2 School of Public Health, Curtin University of Technology, Bentley, WA, Australia Introduction: Type 1 diabetes (T1D) is associated with accelerated atherosclerosis and a 3–4-fold increase in cardiovascular disease (CVD) risk as compared with the non-diabetic population. The paradox of T1D is that despite increased CVD risk, classic fasting lipid indices (elevated low density lipoprotein cholesterol, low concentration of high density lipoprotein cholesterol), are often comparable to those of a healthy population. Furthermore, there is no associated increase in other cardiovascular risk factors such as obesity, smoking or hypertension in T1D. Recent research from our group has shown that chylomicron remnant metabolism may be altered in individuals with longstanding type 1 diabetes even in the absence of classic dyslipidemia. In T1D, arterial vessels are characterized by intimal thickening, smooth muscle cell proliferation, increased expression of extracellular proteoglycans and accumulation of glycated proteins. Recent data suggests that hyperglycaemia and insulin deficiency facilitates the entrapment of apoB and apoE-containing atherogenic lipoproteins in the arterial sub-endothelial matrix. However, there is still lack of direct evidence to implicate the role of hyperglycemia and concomitant glycation of extracellular matrix components causative to preferential cholesterol arterial retention. Objectives: To study the contribution of glycated matrix components on the retention of chylomicron remnants using both an ex vivo and an in vitro approach.
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Methods: Remnant lipoproteins were generated endogenously in vivo via surgical rabbit hepatectomy procedure using chylomicrons collected from lymph cannulated donor control rats. Cy5 labelled remnant lipoproteins were perfused ex vivo in the carotid vessels of control and diabetic (streptozotocin induced diabetes) rats. The binding of remnant lipoproteins in arteries of T1D rats ex vivo was determined using immunohistochemistry and semi-quantitative fluorescent confocal microscopy. The binding of remnants to recombinant biglycan and glycated biglycan was assessed using solid phase binding assay. Results: Remnants bound to human recombinant biglycan was associated with a 1.9-fold higher concentration of cholesterol relative that bound for LDL at Bmax (35.4 ± 1.0 vs 18.26 ± 3.0 g/ml cholesterol per g/ml apoB, respectively; p < 0.001). An additional 2.3-fold greater binding capacity of remnants to glycated biglycan was observed (Bmax = 0.221 ± 0.026 absorbance units) when compared with non-glycated recombinant biglycan (Bmax = 0.096 ± 0.007 absorbance units). Previous ex-vivo data has also shown that carotid vessels from T1D rats show a significant association of remnant lipoproteins and biglycan (co-localization coefficient = 0.78 ± 0.13). Further that remnant lipoproteins and glycated arterial matrix proteins occur in focal clusters ex vivo (co-localization coefficient = 0.71 ± 0.15). We now report that a positive correlation exists (r2 = +0.77) between the amount of remnant lipoproteins bound ex-vivo and the expression of glycated proteins (IHC), suggestive of a non-saturable process. Conclusion: Collectively, data suggests that increased CVD risk in T1D may result from increased exposure of remnant lipoproteins to the vasculature and that glycation may enhance the deposition of lipoprotein-derived cholesterol. We conclude that impaired metabolism of remnant lipoproteins in T1D may contribute to the deposition of cholesterol in arterial tissue and accelerate the progression of atherosclerosis. doi:10.1016/j.atherosclerosissup.2010.04.030
CLA (p < 0.05) or the VA + CLA diet (p < 0.001) relative to controls. Conclusion: Combination of VA and CLA results in a synergistic improvement of fasting and post-prandial lipid metabolism in the JCR:LA-cp rat. Combination of both VA and CLA may in part contribute to the hypolipidemic benefits on circulating dyslipidemia and hepatic steatosis in this rat model. doi:10.1016/j.atherosclerosissup.2010.04.029 Abstract:24 Increased Arterial Exposure to Remnant Lipoproteins Leads to Enhanced Deposition of Cholesterol and Binding to Glycated Extracellular Matrix Proteoglycans R. Mangat 1 , Y. Wang 1 , R.R. Uwiera 1 , D.F. Vine 1 , J.C.L. Mamo 2 , S.D. Proctor 1 1 Alberta
Institute for Human Nutrition, University of Alberta, Edmonton, Canada 2 School of Public Health, Curtin University of Technology, Bentley, WA, Australia Introduction: Type 1 diabetes (T1D) is associated with accelerated atherosclerosis and a 3–4-fold increase in cardiovascular disease (CVD) risk as compared with the non-diabetic population. The paradox of T1D is that despite increased CVD risk, classic fasting lipid indices (elevated low density lipoprotein cholesterol, low concentration of high density lipoprotein cholesterol), are often comparable to those of a healthy population. Furthermore, there is no associated increase in other cardiovascular risk factors such as obesity, smoking or hypertension in T1D. Recent research from our group has shown that chylomicron remnant metabolism may be altered in individuals with longstanding type 1 diabetes even in the absence of classic dyslipidemia. In T1D, arterial vessels are characterized by intimal thickening, smooth muscle cell proliferation, increased expression of extracellular proteoglycans and accumulation of glycated proteins. Recent data suggests that hyperglycaemia and insulin deficiency facilitates the entrapment of apoB and apoE-containing atherogenic lipoproteins in the arterial sub-endothelial matrix. However, there is still lack of direct evidence to implicate the role of hyperglycemia and concomitant glycation of extracellular matrix components causative to preferential cholesterol arterial retention. Objectives: To study the contribution of glycated matrix components on the retention of chylomicron remnants using both an ex vivo and an in vitro approach.
77
Methods: Remnant lipoproteins were generated endogenously in vivo via surgical rabbit hepatectomy procedure using chylomicrons collected from lymph cannulated donor control rats. Cy5 labelled remnant lipoproteins were perfused ex vivo in the carotid vessels of control and diabetic (streptozotocin induced diabetes) rats. The binding of remnant lipoproteins in arteries of T1D rats ex vivo was determined using immunohistochemistry and semi-quantitative fluorescent confocal microscopy. The binding of remnants to recombinant biglycan and glycated biglycan was assessed using solid phase binding assay. Results: Remnants bound to human recombinant biglycan was associated with a 1.9-fold higher concentration of cholesterol relative that bound for LDL at Bmax (35.4 ± 1.0 vs 18.26 ± 3.0 g/ml cholesterol per g/ml apoB, respectively; p < 0.001). An additional 2.3-fold greater binding capacity of remnants to glycated biglycan was observed (Bmax = 0.221 ± 0.026 absorbance units) when compared with non-glycated recombinant biglycan (Bmax = 0.096 ± 0.007 absorbance units). Previous ex-vivo data has also shown that carotid vessels from T1D rats show a significant association of remnant lipoproteins and biglycan (co-localization coefficient = 0.78 ± 0.13). Further that remnant lipoproteins and glycated arterial matrix proteins occur in focal clusters ex vivo (co-localization coefficient = 0.71 ± 0.15). We now report that a positive correlation exists (r2 = +0.77) between the amount of remnant lipoproteins bound ex-vivo and the expression of glycated proteins (IHC), suggestive of a non-saturable process. Conclusion: Collectively, data suggests that increased CVD risk in T1D may result from increased exposure of remnant lipoproteins to the vasculature and that glycation may enhance the deposition of lipoprotein-derived cholesterol. We conclude that impaired metabolism of remnant lipoproteins in T1D may contribute to the deposition of cholesterol in arterial tissue and accelerate the progression of atherosclerosis. doi:10.1016/j.atherosclerosissup.2010.04.030