- Email: [email protected]
2.W14.3 Impaired fibrinolysis and the risk of CHD
Tuesday 7 October 1997: Workshops W1.5 Triglyceride-rich lipoproteins patients. Premature CHD has been proved in 3 patients. In the treatment we used the diet only at 4 patients. Statins we used at 5 patients and fibrates in 1 case. Combination of statin and resin has been used at 4, statin and fibrate as well fibrate resin combinations were used at one patient.
W14 COAGULATION AND FIBRINOLYSIS 2 W EII
14 1
Marie-Claude Paris, France
Thrombm Guillin,
interactions Martine
with
Jandrot-Penus.
vascular
and non vascular
Faculte’ Xavier
Bichat,
cells 75018,
Thrombin, a serine proteinase generated at sites of vascular injury, activates a number of vascular and non vascular cells and elicits a large variety of responses. Thrombin is the most potent physiological activator of platelets, induces proliferation of vascular smooth muscle cells and fibroblasts, stimulates endothelial cells to produce several mediators and induces neutrophil adhesion to the endothelium. Thrombin stimulates other cell types outside the vasculature, such as neuronal or tumor cells. Via its pleiotropic cellular effects, thrombin is not only involved in haemostasis and thrombosis, but also in various physiopathological processes, such as inflammation, tissue remodelling, wound healing and atherosclerosis. Thrombin appears to elicit cellular responses largely, if not exclusively, through proteolytically activated receptor(s). PARS represent a subset in the larger family of seven transmembrane domains G protein-coupled receptors. A single cleavage within the N-terminal exodomain of the prototypic thrombin receptor, PAR-l, unmasks a new N-terminus that binds a specific region on the receptor to trigger activation. A second thrombin receptor belonging to the same family, PAR-3, presents both similarities and differences with PAR-l in its mode of activation. The quantitative and qualitative differences in responses of various cell types to thrombin could be accounted for by differences in tissue distribution of PAR-l and PAR-3, or by coexpression of PAR-l and/or PAR-3 with other thrombin binding proteins, upregulating (GPlb) or downregulating (Thrombomodulin) cell activation. A cross-talk between the thrombin receptors would also be an exciting possibility.
I 2 W14.2
Chronic plaque growth or acute rupture? of vascular connective tissue remodelling
Adrian0 M. Henney. Dept. of Cardiovascular Wellcome Trust Centre for Human Genetics,
Medicine, University of Oxfkd, Oxford OX3 7BN, UK
During the evolution of atherosclerotic lesions, there is continual reshaping and reconstruction of the vessel wall, which will inevitably affect both its cellular and extracellular components. Over many years, the migration and proliferation of cells, the accumulation of lipid in the vessel wall and the extensive deposition and modification of the connective tissue matrix will contribute to lesion growth. This process of vascular connective tissue remodelling is controlled by a complex network of cell-cell and cell-matrix interactions. Pathological studies have described a wide spectrum of structural architecture in atherosclerotic plaques which suggests that, with time, the vascular connective tissue matrix is extensively modified during atherogenesis. This modification, involving both the deposition and removal of extracellular matrix macromolecules, is likely to be a major mechanism contributing to the progression of atherosclerosis. Throughout this process, the net effect on the matrix depends on the balance snuck between synthesis and degradation. This will be affected not only by the distribution locally of smooth muscle cells and macrophages, but also by the control of expression of genes involved in matrix metabolism. On the one hand, shifting the balance in favour of matrix deposition leads to chronic lesion growth and significant stenosis; whilst on the other, excess degradation tends to create lesions with relatively weak, thin caps which are vulnerable to intimal tearing, the commonest event initiating coronary thrombosis. We have been interested in studying these remodelling mechanisms, focusing in particular on one family of enzymes, the matrix metalloproteinases, and their natural inhibitors, the TIMPs. Most of these enzymes are dependant on plasmin for activation, creating a functional overlap with the fibrinolytic cascade. There is abundant evidence implicating these proteins in vascular matrix remodelling during atherogenesis. Our molecular genetic strategies to study how inter-individual variation in the control of expression and activity of these proteins might contribute to more rapid progression of disease and also to plaque disruption are shedding new light on the importance of these proteins in atherogenesis.
Symposium
Impaired
2.W14.3
Irene Juhan-V&ue,
fibrinolysis Marie
Christine
and the risk of CHD Alessi.
CHU
ZImone,
Marseille,
France
The impairment of the fibrinolytic system, which leads to fibrin deposit and is involved in proliferation and migration of vascular cells, could be a prime candidate for the development of atherothrombosis. Recent resclts of several prospective studies are in favor of this hypothesis. A decreased plasma fibrinolytic activity (FA) is predictive of coronary events in young men (Northwick Park Heart Study). An increased plasma concentration of the main fibrinolytic inhibitor, PAI- is predictive of myocardial infarction (MI) in patients with Angina (ECAT Angina Pectotis Study). An increased t-PA antigen concentration (which reflects mainly PAI-l/t-PA complexes) is predictive of MI in healthy subjects (Physicians’ Health Study) and in angina patients (ECAT). The impairment of the fibrinolytic system is mainly related to the phnimetabolic syndrome called insulin resistance (IR). Many studies have shown that FA, PAIor t-PA antigen levels (PAI- 1 being the denominating factor) are strongly correlated (in transversal and interventional studies) with the multiple components of this syndrome (body mass index, waist on hip ratio, insulin, triglyceride, HDL cholesterol and blood pressure...). The prognostic value of PAIfor coronary events disappears after adjustment for insulin resistance markers, whereas the prognostic value of t-PA antigen disappears after additional adjustment for inflammation markers (ECAT). The mechanisms responsible for the alterations of the fibrinolytic system in IR are not fully understood. The role of adipose tissue, in particular of omental fat, in PAIproduction, has recently been emphasized, with a stimulating effect of TWb. A genetic control of plasma PAIlevels has also been shown involving a 4 G/5 G polymorphism in the promoter region of the PAIgene, the 4G allele being :accomprmied by higher plasma PAI- levels. However in healthy male subjects, the contribution of PAI- gene polymorphism in plasma PAIconcentration is weak compared to the influence of the metabolic status. Taken together, these results support the notion that PAI- could be a link between obesity, insulin resistance and cardiovascular disease. 2 rzl
W 14 4
Tissue
factor
- role in coagulation
and angiogenesis
P.P. Nawroth, Y. Zhang, A. Bierhaus, F. Qiu, J. Chen, K. Nakagawa, H. BBhrer, D. Stem, E. Martin, R. Ziegler. Dept. Medicine and Anesthesiology, Univ. Heidelberg, Germany
The yin and yang
11th International
111
Tissue Factor (TF) is the most important initiator of coagulation in sepsis. Intravenous somatic gene transfer with antisense TF cDNA into mice prior to injection of endotoxin can reduce the lethality of endotoxin and the activation of coagulation. Similar effects are achieved with intravenous somatic gene transfer using IkB (the inhibitor of NFkB). Thus endotoxin mediated induction of TF transcription plays an important role in the activation of coagulation and lethality of sepsis. TF has an additional role in tumor biology. It is not only important for tumor metastasis, but also for angiogenesis. Overexpression of TF in murine tumors leads to an increased expression of VEGF in vitro and increased tumor angiogenesis in vivo. Most of the mitogenic activity of TF overexpressing tumor cells IS VEGE Nuclear run on studies showed that TF induces increased VEGF transcription. Thus TF has a dual role: As receptor for Factor VII it initiates coagulation and as an regulator of angiogenesis it induces VEGF in tumor cells.
W 15 TRIGLYCERIDE-RICH
I
2 W 15.1
LIPOPROTEINS
Diierent approaches to tbe detection triglyceride-rich lipoprotein remnants
Jeffrev S. C:&, Jean Davignon. Hyperlipidemia Research Group, Clinical Research Institute
and quantiftcation
a&Atherosclerosis Quebec,
of Montreal,
of
Canada
Both clinical and laboratory studies have implicated plasma niglyceriderich lipoprotein (TRL) remnants in the pathogenesis of atherosclerosis and thrombosis. Remnant lipoproteins, formed through the lipolysis of intestinal chylomicrons or hepatic very low density lipoproteins (VLDL), are however difficult to detect in human plasma, since they are cleared very rapidly from the circulation or are efficiently converted to LDL. Furthermore, despite their reduced size and triglyceride content, they are difficult to differentiate from their newly-secreted precursors. A number of different biochemical
on Atherosclerosis,
Paris,
October
1997
W14 COAGULATION AND FIBRINOLYSIS 2 W EII
14 1
Marie-Claude Paris, France
Thrombm Guillin,
interactions Martine
with
Jandrot-Penus.
vascular
and non vascular
Faculte’ Xavier
Bichat,
cells 75018,
Thrombin, a serine proteinase generated at sites of vascular injury, activates a number of vascular and non vascular cells and elicits a large variety of responses. Thrombin is the most potent physiological activator of platelets, induces proliferation of vascular smooth muscle cells and fibroblasts, stimulates endothelial cells to produce several mediators and induces neutrophil adhesion to the endothelium. Thrombin stimulates other cell types outside the vasculature, such as neuronal or tumor cells. Via its pleiotropic cellular effects, thrombin is not only involved in haemostasis and thrombosis, but also in various physiopathological processes, such as inflammation, tissue remodelling, wound healing and atherosclerosis. Thrombin appears to elicit cellular responses largely, if not exclusively, through proteolytically activated receptor(s). PARS represent a subset in the larger family of seven transmembrane domains G protein-coupled receptors. A single cleavage within the N-terminal exodomain of the prototypic thrombin receptor, PAR-l, unmasks a new N-terminus that binds a specific region on the receptor to trigger activation. A second thrombin receptor belonging to the same family, PAR-3, presents both similarities and differences with PAR-l in its mode of activation. The quantitative and qualitative differences in responses of various cell types to thrombin could be accounted for by differences in tissue distribution of PAR-l and PAR-3, or by coexpression of PAR-l and/or PAR-3 with other thrombin binding proteins, upregulating (GPlb) or downregulating (Thrombomodulin) cell activation. A cross-talk between the thrombin receptors would also be an exciting possibility.
I 2 W14.2
Chronic plaque growth or acute rupture? of vascular connective tissue remodelling
Adrian0 M. Henney. Dept. of Cardiovascular Wellcome Trust Centre for Human Genetics,
Medicine, University of Oxfkd, Oxford OX3 7BN, UK
During the evolution of atherosclerotic lesions, there is continual reshaping and reconstruction of the vessel wall, which will inevitably affect both its cellular and extracellular components. Over many years, the migration and proliferation of cells, the accumulation of lipid in the vessel wall and the extensive deposition and modification of the connective tissue matrix will contribute to lesion growth. This process of vascular connective tissue remodelling is controlled by a complex network of cell-cell and cell-matrix interactions. Pathological studies have described a wide spectrum of structural architecture in atherosclerotic plaques which suggests that, with time, the vascular connective tissue matrix is extensively modified during atherogenesis. This modification, involving both the deposition and removal of extracellular matrix macromolecules, is likely to be a major mechanism contributing to the progression of atherosclerosis. Throughout this process, the net effect on the matrix depends on the balance snuck between synthesis and degradation. This will be affected not only by the distribution locally of smooth muscle cells and macrophages, but also by the control of expression of genes involved in matrix metabolism. On the one hand, shifting the balance in favour of matrix deposition leads to chronic lesion growth and significant stenosis; whilst on the other, excess degradation tends to create lesions with relatively weak, thin caps which are vulnerable to intimal tearing, the commonest event initiating coronary thrombosis. We have been interested in studying these remodelling mechanisms, focusing in particular on one family of enzymes, the matrix metalloproteinases, and their natural inhibitors, the TIMPs. Most of these enzymes are dependant on plasmin for activation, creating a functional overlap with the fibrinolytic cascade. There is abundant evidence implicating these proteins in vascular matrix remodelling during atherogenesis. Our molecular genetic strategies to study how inter-individual variation in the control of expression and activity of these proteins might contribute to more rapid progression of disease and also to plaque disruption are shedding new light on the importance of these proteins in atherogenesis.
Symposium
Impaired
2.W14.3
Irene Juhan-V&ue,
fibrinolysis Marie
Christine
and the risk of CHD Alessi.
CHU
ZImone,
Marseille,
France
The impairment of the fibrinolytic system, which leads to fibrin deposit and is involved in proliferation and migration of vascular cells, could be a prime candidate for the development of atherothrombosis. Recent resclts of several prospective studies are in favor of this hypothesis. A decreased plasma fibrinolytic activity (FA) is predictive of coronary events in young men (Northwick Park Heart Study). An increased plasma concentration of the main fibrinolytic inhibitor, PAI- is predictive of myocardial infarction (MI) in patients with Angina (ECAT Angina Pectotis Study). An increased t-PA antigen concentration (which reflects mainly PAI-l/t-PA complexes) is predictive of MI in healthy subjects (Physicians’ Health Study) and in angina patients (ECAT). The impairment of the fibrinolytic system is mainly related to the phnimetabolic syndrome called insulin resistance (IR). Many studies have shown that FA, PAIor t-PA antigen levels (PAI- 1 being the denominating factor) are strongly correlated (in transversal and interventional studies) with the multiple components of this syndrome (body mass index, waist on hip ratio, insulin, triglyceride, HDL cholesterol and blood pressure...). The prognostic value of PAIfor coronary events disappears after adjustment for insulin resistance markers, whereas the prognostic value of t-PA antigen disappears after additional adjustment for inflammation markers (ECAT). The mechanisms responsible for the alterations of the fibrinolytic system in IR are not fully understood. The role of adipose tissue, in particular of omental fat, in PAIproduction, has recently been emphasized, with a stimulating effect of TWb. A genetic control of plasma PAIlevels has also been shown involving a 4 G/5 G polymorphism in the promoter region of the PAIgene, the 4G allele being :accomprmied by higher plasma PAI- levels. However in healthy male subjects, the contribution of PAI- gene polymorphism in plasma PAIconcentration is weak compared to the influence of the metabolic status. Taken together, these results support the notion that PAI- could be a link between obesity, insulin resistance and cardiovascular disease. 2 rzl
W 14 4
Tissue
factor
- role in coagulation
and angiogenesis
P.P. Nawroth, Y. Zhang, A. Bierhaus, F. Qiu, J. Chen, K. Nakagawa, H. BBhrer, D. Stem, E. Martin, R. Ziegler. Dept. Medicine and Anesthesiology, Univ. Heidelberg, Germany
The yin and yang
11th International
111
Tissue Factor (TF) is the most important initiator of coagulation in sepsis. Intravenous somatic gene transfer with antisense TF cDNA into mice prior to injection of endotoxin can reduce the lethality of endotoxin and the activation of coagulation. Similar effects are achieved with intravenous somatic gene transfer using IkB (the inhibitor of NFkB). Thus endotoxin mediated induction of TF transcription plays an important role in the activation of coagulation and lethality of sepsis. TF has an additional role in tumor biology. It is not only important for tumor metastasis, but also for angiogenesis. Overexpression of TF in murine tumors leads to an increased expression of VEGF in vitro and increased tumor angiogenesis in vivo. Most of the mitogenic activity of TF overexpressing tumor cells IS VEGE Nuclear run on studies showed that TF induces increased VEGF transcription. Thus TF has a dual role: As receptor for Factor VII it initiates coagulation and as an regulator of angiogenesis it induces VEGF in tumor cells.
W 15 TRIGLYCERIDE-RICH
I
2 W 15.1
LIPOPROTEINS
Diierent approaches to tbe detection triglyceride-rich lipoprotein remnants
Jeffrev S. C:&, Jean Davignon. Hyperlipidemia Research Group, Clinical Research Institute
and quantiftcation
a&Atherosclerosis Quebec,
of Montreal,
of
Canada
Both clinical and laboratory studies have implicated plasma niglyceriderich lipoprotein (TRL) remnants in the pathogenesis of atherosclerosis and thrombosis. Remnant lipoproteins, formed through the lipolysis of intestinal chylomicrons or hepatic very low density lipoproteins (VLDL), are however difficult to detect in human plasma, since they are cleared very rapidly from the circulation or are efficiently converted to LDL. Furthermore, despite their reduced size and triglyceride content, they are difficult to differentiate from their newly-secreted precursors. A number of different biochemical
on Atherosclerosis,
Paris,
October
1997