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Impaired endothelial function in healthy elderly subjects is not restored by atorvastatin
Posters 21. Vascular Function ~
STRUCTURAL LOSS OF FUNCTIONAL CAPILLARIES IN FAMILIAL COMBINED HYPERLIPIDEMIA, RELATED TO LIPOPROTEIN REMNANTS
E.T.R Keulen, N.C. Schaper, LM.LR van Lin, I. Lutgens, K. Rijkers, A.J.H.M. Houben, G.M. Dallinga-Thie 1, TW.A. de Bruin. University
Hospital Maastricht, Dep. of Medicine, CARIM, Maastricht; 1University Medical Centre Utrecht, Dep. of Cardiovascular Medicine, Utrecht, The Netherlands Subjects with Familial Combined Hyperlipidemia (FCHL) are often insulin resistant and prone to develop dyslipidemic hypertension. In hypertensive as well as in normotensive healthy subjects, impaired capillary recruitment has been proposed as a missing link between blood pressure and insulin resistance. However, the possible role of lipids was not taken into account. The aim of the present study was to evaluate microvascular function in FCHL. We also looked at the possible role of lipids, in particular remnant lipoproteins, blood pressure values, and surrogate markers of insulin resistance on capillary density. Forty-five age-matched subjects participated in the present study: 20 (10 males) hyperlipidemic, normotensive FCHL subjects and 25 (12 males) healthy controls. Capillary density was measured, by capillary microscopy, just above the finger nailfold (field of 1.6 mm2), before and after 4 minutes of arterial occlusion. Remnant lipoprotein particles cholesterol (RLP-c) concentration was measured after separation on an anti-apoB and anti-apoA1 immuno-affinity column. Comparisons between groups were calculated by gender specific manner (Mann-Whitney U test). The basal number of capillaries (BC) was significantly lower in FCHL men compared to healthy men, 113.7+15.1 vs. 132.0+18.0, p = 0.02. Moreover, the post-occlusive number of capillaries (POC) was significantly reduced in FCHL men relative to healthy controls, 123.04-19.1 vs. 142.3 + 18.3, p = 0.03. POC was inversely correlated with total cholesterol (r = -0.61, p < 0.005), log triglyceride (r = -0.52, p < 0.05), logRLP-c (r = -0.51, p < 0.05) and log insulin (r = -0.48, p < 0.05). Stepwise backward multivariate analyses revealed that logRLP-c was the only significant, independent, contributor to POC. In women, no significant correlations were observed. FCHL men demonstrate a reduction in capillary density in the skin, which is related to increased levels of renmant lipoproteins. When lipids were taken into account, no relationship was observed between capillary density, blood pressure, and insulin resistance. Our results are compatible with a structural loss of functional capillaries in FCHL. The exact role of this abnormality in FCHL remains to be elucidated.
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IMPAIRED ENDOTHELIAL FUNCTION IN HEALTHY ELDERLY SUBJECTS IS NOT RESTORED BY ATORVASTATIN
A.W.E. Weverling-Rijnsburger, G.J. Blauw. Department General Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands Introduction: Endothelial dysfunction is associated with atherosclerosis and cardiovascular risk factors. It has been shown that statines have beneficial effects on cardiovascular mortality, and endothelial function. It was the aim of this study to whether endothelial dependent vasodilation is impaired by increasing age and whether this effect could be influenced by treatment with atorvastatin. Methodology: We selected 7 young (mean age 21.8 years) and 8 elderly (mean age 80.1 years) healthy volunteers. Both groups were non-smokers, had a normal ECG and blood pressure, without any sign and symptoms of cardiovascular disease. The volunteers were measured on two days, with six weeks of atorvastatin treatment in between. The forearm blood flow (FBF) was measured by computerized venous occlusion plethysmogmphy. Drugs were infused intra-arterially, acetylcholine (30 and 90 ng/kg/min) and serotonine (5HT 0.3 and 0.9 ng/kg/min) as endothelium dependent vasodilators and sodium nitroprusside (30 and 90 ng/kg/min) as an endothelium independent vasodilator in a random order. Blood pressure, heart rate and FBF measured 2 minutes before the start of each dose infusion and during the last 2 minutes of the infusion. Results: At baseline the serum cholesterol level was significantly different between both groups, 3.9 mmol/L in the young and 5.4 mmol/L in the elderly group. After treatment with atorvastatin it decreased with 40% in both groups. At baseline FBF was significant lower in the elderly compared with the younger volunteers (2.5 versus 4.5 mL/min/100 mL foream tissue, respectively). Both the vasodilator responses to acethylcholine and 5HT were significantly lower in elderly volunteers, compared to the younger group,
143
while the response to sodium nilxoprusside was similar in both age groups. Treatment with atorvastatin does not influences these vascular responses. Conclusions: Elderly healthy volunteers have impaired endothelial function which is not restored by treatment with atorvastatin.
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ENDOTHELIAL VASODILATORY FUNCTION IS ASSOCIATED WITH CIRCULATING APOLIPOPROTEIN B AND HDL, BUT NOT WITH LDL PARTICLE SIZE OR ANTIBODIES AGAINST OXIDIZED LDL
E Steer, J. Hulthe, J. Millg~lgard, M.D. Sarabi, B. Vessby, L. Lind.
Departments of Medical Sciences and Public Health and Caring Sciences, University Hospital, S-751 85 Uppsala; Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden Endothelium-dependent vasodilation, LDL particle size, and antibodies against oxidized LDL (oxLDLab) have been shown to be related to atherosclerosis and cardiovascular disease. In this study, we investigated if LDL particle size, oxLDLab, apolipoproteins, and lipoproteins are related to endothelial vasodilatory function in a population sample of 59 apparently healthy subjects aged 20 to 69. Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV) were studied in the forearm during local administration of methachotine chloride (2 and 4 ~tg/min) and sodium nitroprusside (5 and 10 [xg/min). Forearm blood flow was determined with venous occlusion plethysmography. In multiple stepwise regression analyses, neither oxLDLab nor small LDL particles were predictive of endothelial vasodilatory function. Instead, a high apolipoprotein B level was an independent predictor of both attenuated EDV and EIDV (p < 0.01 and p < 0.05 respectively). HDL cholesterol, on the other hand, was the only lipid variable being significantly related to the EDV to EIDV ratio, an index of endothelial vasodilatory function (r = 0.32, p < 0.05). In conclusion, the inverse associations between apolipoprotein B and both EDV and EIDV indicate that apolipoprotein B might be an early marker of structural vascular changes in healthy subjects, while HDL seems to be more specifically related to endothelial vasodilatory function.
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DIABETIC LOW DENSITY LIPOPROTEIN (LDL) INHIBITS CELL CYCLE PROGRESSION VIA THE STATS/p21TM PATHWAY
M.E Brizzi 1, E Dentelli 1, M. Pavan 1, A. Rosso 1, L. Formato 1, R. Gambino 1, M. Cassader 1, A. Castelli 1, P. Defilippi2, G. Pagano 1, L. Pegoraro 1. I Department of Internal Medicine and 2Department of
Genetics, Biology and Cellular Biochemistry, University of Torino, 10126 Torino, Italy Modified low-density lipoprotein (LDL) is a major cause of injury to the endothelium in diabetes. Our previous data demonstrate that, unlike native LDL (n-LDL), diabetic LDL (dm-LDL) inhibits cell cycle entry and progression into S phase in human umbilical endothelial cells (HUVEC). To dissect the molecular mechanisms involved in such inhibition, we analyzed the level of molecules involved in cell-cycle machinery, i.e. the cyclin-dependent kinase inhibitor p21TM that has been reported to be a target of the Signal Transducers and Activator of Transcription (STATs). Treatment of HUVEC with dm-LDL, possibly via advanced glycation endproduct receptor (RAGE) engagement, increases the level of p21TM protein expression in contrast with the reduced expression observed in response to n-LDL or bFGE In the present report we demonstrate that, unlike n-LDL, dm-LDL induces a transient phosphorylation of STAT5 proteins in HUVEC and consistent with the role for the STAT5 pathway in regulation of gene transcription dm-LDL induces the formation of STAT5-containing complexes. Stable transfection of the dominant ne[~ative form of STAT5B, but not STAT5A, affects upregulation of p21 war in response to dm-LDL in ECV 304 cells, suggesting that such regulation occurs through STAT5B pathway. Similar results were obtained by infecting HUVEC with viruses produced by a retroviral vector coding for the dominant negative STAT5 proteins. The ability of the infected HUVEC to entry and progress into the cell cycle in response to dm-LDL was also evaluated.
72nd EAS Congress
STRUCTURAL LOSS OF FUNCTIONAL CAPILLARIES IN FAMILIAL COMBINED HYPERLIPIDEMIA, RELATED TO LIPOPROTEIN REMNANTS
E.T.R Keulen, N.C. Schaper, LM.LR van Lin, I. Lutgens, K. Rijkers, A.J.H.M. Houben, G.M. Dallinga-Thie 1, TW.A. de Bruin. University
Hospital Maastricht, Dep. of Medicine, CARIM, Maastricht; 1University Medical Centre Utrecht, Dep. of Cardiovascular Medicine, Utrecht, The Netherlands Subjects with Familial Combined Hyperlipidemia (FCHL) are often insulin resistant and prone to develop dyslipidemic hypertension. In hypertensive as well as in normotensive healthy subjects, impaired capillary recruitment has been proposed as a missing link between blood pressure and insulin resistance. However, the possible role of lipids was not taken into account. The aim of the present study was to evaluate microvascular function in FCHL. We also looked at the possible role of lipids, in particular remnant lipoproteins, blood pressure values, and surrogate markers of insulin resistance on capillary density. Forty-five age-matched subjects participated in the present study: 20 (10 males) hyperlipidemic, normotensive FCHL subjects and 25 (12 males) healthy controls. Capillary density was measured, by capillary microscopy, just above the finger nailfold (field of 1.6 mm2), before and after 4 minutes of arterial occlusion. Remnant lipoprotein particles cholesterol (RLP-c) concentration was measured after separation on an anti-apoB and anti-apoA1 immuno-affinity column. Comparisons between groups were calculated by gender specific manner (Mann-Whitney U test). The basal number of capillaries (BC) was significantly lower in FCHL men compared to healthy men, 113.7+15.1 vs. 132.0+18.0, p = 0.02. Moreover, the post-occlusive number of capillaries (POC) was significantly reduced in FCHL men relative to healthy controls, 123.04-19.1 vs. 142.3 + 18.3, p = 0.03. POC was inversely correlated with total cholesterol (r = -0.61, p < 0.005), log triglyceride (r = -0.52, p < 0.05), logRLP-c (r = -0.51, p < 0.05) and log insulin (r = -0.48, p < 0.05). Stepwise backward multivariate analyses revealed that logRLP-c was the only significant, independent, contributor to POC. In women, no significant correlations were observed. FCHL men demonstrate a reduction in capillary density in the skin, which is related to increased levels of renmant lipoproteins. When lipids were taken into account, no relationship was observed between capillary density, blood pressure, and insulin resistance. Our results are compatible with a structural loss of functional capillaries in FCHL. The exact role of this abnormality in FCHL remains to be elucidated.
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IMPAIRED ENDOTHELIAL FUNCTION IN HEALTHY ELDERLY SUBJECTS IS NOT RESTORED BY ATORVASTATIN
A.W.E. Weverling-Rijnsburger, G.J. Blauw. Department General Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands Introduction: Endothelial dysfunction is associated with atherosclerosis and cardiovascular risk factors. It has been shown that statines have beneficial effects on cardiovascular mortality, and endothelial function. It was the aim of this study to whether endothelial dependent vasodilation is impaired by increasing age and whether this effect could be influenced by treatment with atorvastatin. Methodology: We selected 7 young (mean age 21.8 years) and 8 elderly (mean age 80.1 years) healthy volunteers. Both groups were non-smokers, had a normal ECG and blood pressure, without any sign and symptoms of cardiovascular disease. The volunteers were measured on two days, with six weeks of atorvastatin treatment in between. The forearm blood flow (FBF) was measured by computerized venous occlusion plethysmogmphy. Drugs were infused intra-arterially, acetylcholine (30 and 90 ng/kg/min) and serotonine (5HT 0.3 and 0.9 ng/kg/min) as endothelium dependent vasodilators and sodium nitroprusside (30 and 90 ng/kg/min) as an endothelium independent vasodilator in a random order. Blood pressure, heart rate and FBF measured 2 minutes before the start of each dose infusion and during the last 2 minutes of the infusion. Results: At baseline the serum cholesterol level was significantly different between both groups, 3.9 mmol/L in the young and 5.4 mmol/L in the elderly group. After treatment with atorvastatin it decreased with 40% in both groups. At baseline FBF was significant lower in the elderly compared with the younger volunteers (2.5 versus 4.5 mL/min/100 mL foream tissue, respectively). Both the vasodilator responses to acethylcholine and 5HT were significantly lower in elderly volunteers, compared to the younger group,
143
while the response to sodium nilxoprusside was similar in both age groups. Treatment with atorvastatin does not influences these vascular responses. Conclusions: Elderly healthy volunteers have impaired endothelial function which is not restored by treatment with atorvastatin.
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ENDOTHELIAL VASODILATORY FUNCTION IS ASSOCIATED WITH CIRCULATING APOLIPOPROTEIN B AND HDL, BUT NOT WITH LDL PARTICLE SIZE OR ANTIBODIES AGAINST OXIDIZED LDL
E Steer, J. Hulthe, J. Millg~lgard, M.D. Sarabi, B. Vessby, L. Lind.
Departments of Medical Sciences and Public Health and Caring Sciences, University Hospital, S-751 85 Uppsala; Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden Endothelium-dependent vasodilation, LDL particle size, and antibodies against oxidized LDL (oxLDLab) have been shown to be related to atherosclerosis and cardiovascular disease. In this study, we investigated if LDL particle size, oxLDLab, apolipoproteins, and lipoproteins are related to endothelial vasodilatory function in a population sample of 59 apparently healthy subjects aged 20 to 69. Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV) were studied in the forearm during local administration of methachotine chloride (2 and 4 ~tg/min) and sodium nitroprusside (5 and 10 [xg/min). Forearm blood flow was determined with venous occlusion plethysmography. In multiple stepwise regression analyses, neither oxLDLab nor small LDL particles were predictive of endothelial vasodilatory function. Instead, a high apolipoprotein B level was an independent predictor of both attenuated EDV and EIDV (p < 0.01 and p < 0.05 respectively). HDL cholesterol, on the other hand, was the only lipid variable being significantly related to the EDV to EIDV ratio, an index of endothelial vasodilatory function (r = 0.32, p < 0.05). In conclusion, the inverse associations between apolipoprotein B and both EDV and EIDV indicate that apolipoprotein B might be an early marker of structural vascular changes in healthy subjects, while HDL seems to be more specifically related to endothelial vasodilatory function.
•
DIABETIC LOW DENSITY LIPOPROTEIN (LDL) INHIBITS CELL CYCLE PROGRESSION VIA THE STATS/p21TM PATHWAY
M.E Brizzi 1, E Dentelli 1, M. Pavan 1, A. Rosso 1, L. Formato 1, R. Gambino 1, M. Cassader 1, A. Castelli 1, P. Defilippi2, G. Pagano 1, L. Pegoraro 1. I Department of Internal Medicine and 2Department of
Genetics, Biology and Cellular Biochemistry, University of Torino, 10126 Torino, Italy Modified low-density lipoprotein (LDL) is a major cause of injury to the endothelium in diabetes. Our previous data demonstrate that, unlike native LDL (n-LDL), diabetic LDL (dm-LDL) inhibits cell cycle entry and progression into S phase in human umbilical endothelial cells (HUVEC). To dissect the molecular mechanisms involved in such inhibition, we analyzed the level of molecules involved in cell-cycle machinery, i.e. the cyclin-dependent kinase inhibitor p21TM that has been reported to be a target of the Signal Transducers and Activator of Transcription (STATs). Treatment of HUVEC with dm-LDL, possibly via advanced glycation endproduct receptor (RAGE) engagement, increases the level of p21TM protein expression in contrast with the reduced expression observed in response to n-LDL or bFGE In the present report we demonstrate that, unlike n-LDL, dm-LDL induces a transient phosphorylation of STAT5 proteins in HUVEC and consistent with the role for the STAT5 pathway in regulation of gene transcription dm-LDL induces the formation of STAT5-containing complexes. Stable transfection of the dominant ne[~ative form of STAT5B, but not STAT5A, affects upregulation of p21 war in response to dm-LDL in ECV 304 cells, suggesting that such regulation occurs through STAT5B pathway. Similar results were obtained by infecting HUVEC with viruses produced by a retroviral vector coding for the dominant negative STAT5 proteins. The ability of the infected HUVEC to entry and progress into the cell cycle in response to dm-LDL was also evaluated.
72nd EAS Congress