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Pericellular plasmin induces smooth muscle cell anoikis
Meilhac ~-~
•]
L I P O P R O T E I N (A) LEVELS IN PATIENTS W I T H M E T A B O L I C SYNDROME
I.V. Medvedeva, T.A. Pugacheva, E.E Dorodneva. Tyumen Medical Academy, Tyumen, Russia
163
INFLUENCE OF C H R O N I C C I G A R E T T E S M O K I N G ON THE POSTPRANDIAL CHANGES OF SERUM LIPID PROFILE
I.V. Medvedeva, T.A. Pugacheva, I.E Sholomov, A.A. Pushnikov, E.E Odishev. Tyumen Medical Academy, Tyumen, Russia
Increased serum lipoprotein (a) level is an independent risk factor for coronary artery disease. We determined serum LP(a) levels and investigated the relationships between LP(a) levels and clinical and biochemical parameters in patients with metabolic syndrome (MS). Methods: 40 subjects with MS (23 women and 17 men, mean age 52,3±1,1 years) were included in this study. The main signs of metabolic syndrome such as diabetes mellitus (type 2) satisfactorily controlled by oral hypoglycemic agents, abdominal obesity (BMI > 29 kg/m2, waist-to-hip ratio > 0.9), arterial hypertension (BP>140/90 mmHg) and dyslipidemia (ItDL cholesterol level <35 mg/dl, triglyceride (TG) level > 200 mg/dl, total cholesterol level > 200 mg/dl) were registered in all patients. Serum LP(a) level was measured by an immunoturbidimetric method (Humalazer-2000). Results: The results of study demonstrated the high frequency of elevated LP(a) levels in the observed patients with MS. The Lp(a) concentration higher than the established conditional standard (30 mg/dl) was determined in 100% patients with MS. The mean of LP(a) levels in patients with MS was 43±,6 mg/dl. We found relationships between LP(a) level and some clinical and biochemical characteristics in patients with MS. By univariate analysis, LP(a) level correlated positively with diastolic blood pressure (p-0,002), fibrinogen level (p-0,016) and fasting glucose level (p-0,028). Significant positive correlation between LP(a) level and other atherogenic plasma factors such as TG and LDL cholesterol has been found. Multiple regression analysis showed that diastolic blood pressure was remained a significant independent predictor of LP(a) concentration in patients with MS.
To assess the influence of chronic cigarette smoking on the postprandial serum lipid profile, standardized oral fat load of the animal origin (unsalted butter, 50 g) was performed in 30 apparently healthy normolipidemic smokers without a family-history of metabolic diseases (men, 3 4±,2 years, BMI 23,1 ±2,0 kg/m2, duration of cigarette smoking 12,9±4,7 years). They were compared with 30 apparently healthy controls (non-smokers) matched for age, sex, BMI and WHR. Fasting TG, total cholesterol, LDL and HDL cholesterol levels in smokers were comparable with those of control subjects. Serum lipid and apolipoprotein levels were analyzed before and in 6 hours after oral fat intake. Data were evaluated by non-parametric statistical analysis (Wilcoxon test). Results: It was determined that post-load TG and apo B levels increased in smokers (p-0,033, p-0,041, respectively). We also observed tendency to TG level increase (p-0,067) in nonsmokers. Considerable changes of antiatherogenic factors of the lipid metabolism (HDL cholesterol and apo A1) were not marked in both groups. Similarly, we did not register significant changes of total cholesterol, LDL cholesterol and LP (a) levels after fat intake in smokers and non-smokers. Conclusion: The received data demonstrate prolonged post-load changes of plasma lipid spectrum of the atherogenic character in smokers. The results suggest that smokers be characterized by more pronounced prolonged alimentary lipaemia that are related to premature coronary atherosclerosis. ~-~
~-f3] I N F L U E N C E OF G L U C O S E C O N T R O L ON THE MAIN PARAMETERS OF SERUM LIPID P R O F I L E AND P L A T E L E T M E M B R A N E S IN PATIENTS W I T H M E T A B O L I C SYNDROME AND TYPE 2 DIABETES M E L L I T U S I.V. Medvedeva, T.A. Pugacheva, E.E Dorodneva. Tyumen Medical Academy, Tyumen, Russia 89 patients with metabolic syndrome (MS) (37 men and 52 women, aged 48,13±,15 years) were included in this study. The MS components such as arterial hypertension (blood pressure ~> 140/90 m m Hg), abdominal obesity (body mass index ~> 26 kg/m2, waist/hip ratio ~>0.9), and dyslipidaemia (HDL-cholesterol level <35 mg/dl, triglyceride level > 200 mg/dl, total cholesterol level > 200 mg/dl) were registered in all examined patients. The type 2 diabetes mellitus (controlled by oral hypoglycemic agents) was the obligatory component in the experimental group. Subjects with MS were grouped according to the state of metabolic control. We compared the lipid profile and the main parameters of platelet membranes in 40 patients with good glucose control (fasting glycemia, 5 5,5 mmol/1, postprandial glycemia, 5 7,0 mmol/1)? 49 patients with suboptimal glucose control (fasting glycemia, 6 6,5 mmol/1, postprandial glycemia, 1 9,0 mmol/1). Plasma lipids, apolipoproteins and the main parameters ofplatelet membranes (lipid composition, state of lipid peroxidation (POL) and antioxidant defence) were thus assessed. Data were evaluated by non-parametric statistical analysis. Results: We observed significantly lower concentrations of TG and LP (a) (p-0,034, p-0,017 respectively) and tendency towards an increased level of HDL-C (p-0,067) in patients fulfilling the criteria of good metabolic control compared to the patients who had suboptimal glycemic control. By univariate analysis, fasting glucose level correlated positively with atherogenic plasma factors such as LP (a) and TG and negatively with HDL cholesterol level. The group of patients with good glucose control showed also significantly lower POL products concentrations (diene conjugates and thiobarbituric acid-reactive substances), higher superoxiddismutase activity (p-0,007) and a-tocopherol level (p-0,002) in platelet membranes than patients with suboptimal glycemic control. Conclusion: A good glucose control improves parameters of serum lipid profile and platelet membranes in patients with MS and type 2 diabetes mellitus.
P E R I C E L L U L A R P L A S M I N INDUCES S M O O T H M U S C L E C E L L ANOIKIS
O. Meilhac, B. Ho-Tin-Noe, E. Angles-Cano, M. Philippe, J.-B. Michel. INSERM Unit 460, Paris, France In contrast with the well explored intracellular signaling pathways involved in physiological anoikis, the extracellular signals able to induce anoikis in pathology remain to be investigated. Smooth muscle cell (SMC) disappearance is involved in the development of several vascular pathologies. Using primary cultures of arterial SMCs, we show that plasmin induces cell retraction and detachment, accompanied by morphological changes characteristic of apoptosis. Similar changes are induced in arterial rings, ex-vivo, by exposure to plasmin and more importantly, in vascular smooth muscle cells (VSMCs) by plasmin generated from plasminogen on the cell surface. The generation of pericellular plasmin is mediated by tissue-type plasminogen activator (t-PA) constitutively expressed by VSMCs, requires binding of plasminogen to the cell surface and is inhibited by epsilonaminocaproic acid (IC50-0.9mM), a competitor of plasminogen binding to membrane glycoproteins. Conversely, alpha-2-antiplasmin which blocks free plasmin in the cell supernatant could not fully prevent anoikis. Cellmediated plasminogen activation leads to fibronectin fragmentation. An MMP inhibitor failed to prevent VSMCs anoikis, arguing for a direct involvement of plasmin in this phenomenon. In conclusion, we show for the first time that pathological anoikis can be triggered by a process that requires functional assembly of the plasminogen activation system on the surface of VSMCs.
73rd EAS Congress
•]
L I P O P R O T E I N (A) LEVELS IN PATIENTS W I T H M E T A B O L I C SYNDROME
I.V. Medvedeva, T.A. Pugacheva, E.E Dorodneva. Tyumen Medical Academy, Tyumen, Russia
163
INFLUENCE OF C H R O N I C C I G A R E T T E S M O K I N G ON THE POSTPRANDIAL CHANGES OF SERUM LIPID PROFILE
I.V. Medvedeva, T.A. Pugacheva, I.E Sholomov, A.A. Pushnikov, E.E Odishev. Tyumen Medical Academy, Tyumen, Russia
Increased serum lipoprotein (a) level is an independent risk factor for coronary artery disease. We determined serum LP(a) levels and investigated the relationships between LP(a) levels and clinical and biochemical parameters in patients with metabolic syndrome (MS). Methods: 40 subjects with MS (23 women and 17 men, mean age 52,3±1,1 years) were included in this study. The main signs of metabolic syndrome such as diabetes mellitus (type 2) satisfactorily controlled by oral hypoglycemic agents, abdominal obesity (BMI > 29 kg/m2, waist-to-hip ratio > 0.9), arterial hypertension (BP>140/90 mmHg) and dyslipidemia (ItDL cholesterol level <35 mg/dl, triglyceride (TG) level > 200 mg/dl, total cholesterol level > 200 mg/dl) were registered in all patients. Serum LP(a) level was measured by an immunoturbidimetric method (Humalazer-2000). Results: The results of study demonstrated the high frequency of elevated LP(a) levels in the observed patients with MS. The Lp(a) concentration higher than the established conditional standard (30 mg/dl) was determined in 100% patients with MS. The mean of LP(a) levels in patients with MS was 43±,6 mg/dl. We found relationships between LP(a) level and some clinical and biochemical characteristics in patients with MS. By univariate analysis, LP(a) level correlated positively with diastolic blood pressure (p-0,002), fibrinogen level (p-0,016) and fasting glucose level (p-0,028). Significant positive correlation between LP(a) level and other atherogenic plasma factors such as TG and LDL cholesterol has been found. Multiple regression analysis showed that diastolic blood pressure was remained a significant independent predictor of LP(a) concentration in patients with MS.
To assess the influence of chronic cigarette smoking on the postprandial serum lipid profile, standardized oral fat load of the animal origin (unsalted butter, 50 g) was performed in 30 apparently healthy normolipidemic smokers without a family-history of metabolic diseases (men, 3 4±,2 years, BMI 23,1 ±2,0 kg/m2, duration of cigarette smoking 12,9±4,7 years). They were compared with 30 apparently healthy controls (non-smokers) matched for age, sex, BMI and WHR. Fasting TG, total cholesterol, LDL and HDL cholesterol levels in smokers were comparable with those of control subjects. Serum lipid and apolipoprotein levels were analyzed before and in 6 hours after oral fat intake. Data were evaluated by non-parametric statistical analysis (Wilcoxon test). Results: It was determined that post-load TG and apo B levels increased in smokers (p-0,033, p-0,041, respectively). We also observed tendency to TG level increase (p-0,067) in nonsmokers. Considerable changes of antiatherogenic factors of the lipid metabolism (HDL cholesterol and apo A1) were not marked in both groups. Similarly, we did not register significant changes of total cholesterol, LDL cholesterol and LP (a) levels after fat intake in smokers and non-smokers. Conclusion: The received data demonstrate prolonged post-load changes of plasma lipid spectrum of the atherogenic character in smokers. The results suggest that smokers be characterized by more pronounced prolonged alimentary lipaemia that are related to premature coronary atherosclerosis. ~-~
~-f3] I N F L U E N C E OF G L U C O S E C O N T R O L ON THE MAIN PARAMETERS OF SERUM LIPID P R O F I L E AND P L A T E L E T M E M B R A N E S IN PATIENTS W I T H M E T A B O L I C SYNDROME AND TYPE 2 DIABETES M E L L I T U S I.V. Medvedeva, T.A. Pugacheva, E.E Dorodneva. Tyumen Medical Academy, Tyumen, Russia 89 patients with metabolic syndrome (MS) (37 men and 52 women, aged 48,13±,15 years) were included in this study. The MS components such as arterial hypertension (blood pressure ~> 140/90 m m Hg), abdominal obesity (body mass index ~> 26 kg/m2, waist/hip ratio ~>0.9), and dyslipidaemia (HDL-cholesterol level <35 mg/dl, triglyceride level > 200 mg/dl, total cholesterol level > 200 mg/dl) were registered in all examined patients. The type 2 diabetes mellitus (controlled by oral hypoglycemic agents) was the obligatory component in the experimental group. Subjects with MS were grouped according to the state of metabolic control. We compared the lipid profile and the main parameters of platelet membranes in 40 patients with good glucose control (fasting glycemia, 5 5,5 mmol/1, postprandial glycemia, 5 7,0 mmol/1)? 49 patients with suboptimal glucose control (fasting glycemia, 6 6,5 mmol/1, postprandial glycemia, 1 9,0 mmol/1). Plasma lipids, apolipoproteins and the main parameters ofplatelet membranes (lipid composition, state of lipid peroxidation (POL) and antioxidant defence) were thus assessed. Data were evaluated by non-parametric statistical analysis. Results: We observed significantly lower concentrations of TG and LP (a) (p-0,034, p-0,017 respectively) and tendency towards an increased level of HDL-C (p-0,067) in patients fulfilling the criteria of good metabolic control compared to the patients who had suboptimal glycemic control. By univariate analysis, fasting glucose level correlated positively with atherogenic plasma factors such as LP (a) and TG and negatively with HDL cholesterol level. The group of patients with good glucose control showed also significantly lower POL products concentrations (diene conjugates and thiobarbituric acid-reactive substances), higher superoxiddismutase activity (p-0,007) and a-tocopherol level (p-0,002) in platelet membranes than patients with suboptimal glycemic control. Conclusion: A good glucose control improves parameters of serum lipid profile and platelet membranes in patients with MS and type 2 diabetes mellitus.
P E R I C E L L U L A R P L A S M I N INDUCES S M O O T H M U S C L E C E L L ANOIKIS
O. Meilhac, B. Ho-Tin-Noe, E. Angles-Cano, M. Philippe, J.-B. Michel. INSERM Unit 460, Paris, France In contrast with the well explored intracellular signaling pathways involved in physiological anoikis, the extracellular signals able to induce anoikis in pathology remain to be investigated. Smooth muscle cell (SMC) disappearance is involved in the development of several vascular pathologies. Using primary cultures of arterial SMCs, we show that plasmin induces cell retraction and detachment, accompanied by morphological changes characteristic of apoptosis. Similar changes are induced in arterial rings, ex-vivo, by exposure to plasmin and more importantly, in vascular smooth muscle cells (VSMCs) by plasmin generated from plasminogen on the cell surface. The generation of pericellular plasmin is mediated by tissue-type plasminogen activator (t-PA) constitutively expressed by VSMCs, requires binding of plasminogen to the cell surface and is inhibited by epsilonaminocaproic acid (IC50-0.9mM), a competitor of plasminogen binding to membrane glycoproteins. Conversely, alpha-2-antiplasmin which blocks free plasmin in the cell supernatant could not fully prevent anoikis. Cellmediated plasminogen activation leads to fibronectin fragmentation. An MMP inhibitor failed to prevent VSMCs anoikis, arguing for a direct involvement of plasmin in this phenomenon. In conclusion, we show for the first time that pathological anoikis can be triggered by a process that requires functional assembly of the plasminogen activation system on the surface of VSMCs.
73rd EAS Congress