Plasminogen Activator Inhibitor 1 and Atherothrombosis

Clinical manifestations of coronary heart disease result principally from the progressive development of atherosclerotic plaques and subsequent thrombus formation. The role of fibrin deposition in the acute thrombotic occlusion of coronary arteries that leads to myocardial infarction has been clearly established (1). Progressive incorporation of fibrin into the vessel wall could also play a role in the development of the atherosclerotic lesion (2-6). Fibrin is a consistent component of human atherosclerotic plaques (6-9) and may contribute to plaque growth by stimulation of smooth muscle cell proliferation (10) and by binding and accumulating with low density lipoprotein, especially lipoprotein (a) (11,12). Hypofibrinolysis leading to decreased removal of fibrin deposits (13) would be a prime candidate for a role in the development of atherothrombosis. Reduced plasma fibrinolytic capacity accompanying atherothrombosis has been attributed to increased levels of plasminogen activator inhibitor 1 (PAI-I ) , the primary physiological inhibitor of t -PA and urokinase . Recen t exper imenta l d a t a have shown tha t increased plasma PAI-1 levels do indeed have a prothrombotic effect. Increased PAI-1 decreases endogenous and exogenous fibrinolysis and increases the extension of thrombosis (14-16), whereas quenching of PAI-1 activity with a specific antibody induces an opposite effect (17). Transgenic mice with overexpression of the human PAI-1 gene develop thrombosis in their extremities (18). Moreover, human PAI-1 deficiency was recently reported as a cause of abnormal bleeding (19). Clinical studies suggest that increased PAI-1 expression is of pathogenic significance and when present in plasma map be considered as a biological risk factor for coronary heart disease; locally, in the atherosclerotic lesion, it could favor a thrombotic phenomenon. This review will evaluate the epidemiological and experimental evidence for a causal role of systemic or local increase in PAI-1 levels in atherothrombosis.

[1]  P. Vague,et al.  Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin. , 1993, The Journal of clinical investigation.

[2]  B. Sobel,et al.  Attenuated Fibrinolysis and Accelerated Atherogenesis in Type II Diabetic Patients , 1993, Diabetes.

[3]  B. Sobel,et al.  Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[4]  J. Saffitz,et al.  Induction of Endothelial Cell Expression of the Plasminogen Activator Inhibitor Type 1 Gene by Thrombosis In Vivo , 1992, Circulation.

[5]  J. Jansson,et al.  von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death , 1992, British heart journal.

[6]  T. Hayashi,et al.  Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells. , 1992, Atherosclerosis.

[7]  Thiennu H. Vu,et al.  Thrombin receptor expression in normal and atherosclerotic human arteries. , 1992, The Journal of clinical investigation.

[8]  D. Loskutoff,et al.  Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  B. Sobel,et al.  Stimulation by Proinsulin of Expression of Plasminogen Activator Inhibitor Type-I in Endothelial Cells , 1992, Diabetes.

[10]  B. Sobel,et al.  Post-transcriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin-like growth factor 1. , 1992, The Journal of biological chemistry.

[11]  K. Huber,et al.  A Decrease in Plasminogen Activator Inhibitor-1 Activity after Successful Percutaneous Transluminal Coronary Angioplasty Is Associated with a Significantly Reduced Risk for Coronary Restenosis , 1992, Thrombosis and Haemostasis.

[12]  B. Sobel,et al.  Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: Implications for vascular disease in hyperinsulinemic states , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Jansson,et al.  von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. , 1991, British heart journal.

[14]  D. Fischman,et al.  Evidence for Reduced Fibrinolytic Activity in Unstable Angina at Rest: Clinical, Biochemical, and Angiographic Correlates , 1991, Circulation.

[15]  R. Medcalf,et al.  Basal Expression and Insulin-mediated Induction of PAI-1 mRNA in Hep G2 Cells , 1991 .

[16]  K. Hajjar,et al.  Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. , 1991, The Journal of biological chemistry.

[17]  B. Sobel,et al.  Mechanisms contributing to increased synthesis of plasminogen activator inhibitor type 1 in endothelial cells by constituents of platelets and their implications for thrombolysis. , 1991, Circulation.

[18]  J. Jansson,et al.  Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. , 1991, European heart journal.

[19]  J. Felber,et al.  Short-term infusions of insulin, triacylglycerol and glucose do not cause acute increases in plasminogen activator inhibitor-1 concentrations in man. , 1990, Clinical science.

[20]  A. Hamsten,et al.  Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. , 1990, Arteriosclerosis.

[21]  S. Suzuki,et al.  Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia. , 1990, American heart journal.

[22]  U. Smith,et al.  Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. , 1990, Metabolism: clinical and experimental.

[23]  A. Lusis,et al.  Dietary regulation of fibrinolytic factors. , 1990, Atherosclerosis.

[24]  K. Marotti,et al.  Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene , 1990, Nature.

[25]  A. Hamsten,et al.  The Fibrinolytic Enzyme System and Its Role in the Etiology of Thromboembolic Disease , 1990, Seminars in thrombosis and hemostasis.

[26]  K. Huber,et al.  Plasminogen Activator Inhibitor-1 Levels in Patients with Chronic Angina Pectoris with or without Angiographic Evidence of Coronary Sclerosis , 1990, Thrombosis and Haemostasis.

[27]  J. Jespersen,et al.  A depression of active tissue plasminogen activator in plasma characterizes patients with unstable angina pectoris who develop myocardial infarction. , 1990, European heart journal.

[28]  U. Smith,et al.  Elevated fibrinogen and plasminogen activator inhibitor (PAI‐1) in hypertension are related to metabolic risk factors for cardiovascular disease , 1990, Journal of internal medicine.

[29]  E. B. Smith,et al.  Fate of fibrinogen in human arterial intima. , 1990, Arteriosclerosis.

[30]  G. Hallmans,et al.  Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a north Swedish population. , 1989, Atherosclerosis.

[31]  P. Bosma,et al.  Plasminogen Activator Inhibitor 1: Biosynthesis and mRNA Level Are Increased by Insulin in Cultured Human Hepatocytes , 1989, Thrombosis and Haemostasis.

[32]  P. Vague,et al.  Fat distribution and plasminogen activator inhibitor activity in nondiabetic obese women. , 1989, Metabolism: clinical and experimental.

[33]  M. Grant,et al.  Fibrinolytic capacity following stimulation with desmopressin acetate in patients with diabetes mellitus. , 1989, Metabolism: clinical and experimental.

[34]  P. Vague,et al.  Increased Plasminogen Activator Inhibitor Activity in Non Insulin Dependent Diabetic Patients – Relationship with Plasma Insulin , 1989, Thrombosis and Haemostasis.

[35]  B. Sobel,et al.  Potential attenuation of fibrinolysis by growth factors released from platelets and their pharmacologic implications. , 1989, The American journal of cardiology.

[36]  M. Alessi,et al.  Plasma Plasminogen Activator Inhibitor‐1 in Angina Pectoris: Influence of Plasma Insulin and Acute‐phase Response , 1989, Arteriosclerosis.

[37]  Josiahn . Wilcox,et al.  Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  K. Huber,et al.  Circadian Fluctuations of Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma of Patients with Unstable Coronary Artery Disease and Acute Myocardial Infarction , 1988, Thrombosis and Haemostasis.

[39]  T. Kooistra,et al.  Insulin Stimulates the Synthesis of Plasminogen Activator Inhibitor 1 by the Human Hepatocellular Cell Line Hep G2 , 1988, Thrombosis and Haemostasis.

[40]  G. Reaven.  Banting lecture 1988. Role of insulin resistance in human disease. , 1988, Diabetes.

[41]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[42]  G. Hallmans,et al.  The effect of body build, diet and endocrine factors on the extrinsic fibrinolytic system in healthy young women. , 1988, Scandinavian journal of clinical and laboratory investigation.

[43]  C. Legnani,et al.  Reduced fibrinolytic response in obese children: Association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1) , 1988 .

[44]  A. Maseri,et al.  Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. , 1988, The American journal of cardiology.

[45]  W. Speiser,et al.  Increased blood fibrinolytic activity after physical exercise: comparative study in individuals with different sporting activities and in patients after myocardial infarction taking part in a rehabilitation sports program. , 1988, Thrombosis research.

[46]  J. Auwerx,et al.  Tissue‐Type Plasminogen Activator Antigen and Plasminogen Activator Inhibitor in Diabetes Mellitus , 1988, Arteriosclerosis.

[47]  P. Vague,et al.  Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. , 1987, Diabete & metabolisme.

[48]  M. Alessi,et al.  Metformin Decreases the High Plasminogen Activator Inhibition Capacity, Plasma Insulin and Triglyceride Levels in Non-Diabetic Obese Subjects , 1987, Thrombosis and Haemostasis.

[49]  Y. Takada,et al.  Relationship between age and plasma t-PA, PA-inhibitor, and PA activity. , 1987, Thrombosis research.

[50]  J. T. ten Cate,et al.  Tissue plasminogen activator activity and inhibition in acute myocardial infarction and angiographically normal coronary arteries. , 1987, The American journal of cardiology.

[51]  T. Saldeen,et al.  Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. , 1987, Journal of the American College of Cardiology.

[52]  E. B. Smith.  Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. , 1986, Clinics in haematology.

[53]  M. Alessi,et al.  Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. , 1986, Metabolism: clinical and experimental.

[54]  T. Kooistra,et al.  Inhibition of plasminogen activators by conditioned medium of human hepatocytes and hepatoma cell line Hep G2. , 1985, The Journal of laboratory and clinical medicine.

[55]  C. B. Childs,et al.  Serum contains a platelet-derived transforming growth factor. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[56]  T. Welborn,et al.  Coronary Heart Disease Incidence and Cardiovascular Mortality in Busselton with Reference to Glucose and Insulin Concentrations , 1979, Diabetes Care.

[57]  R. Stout,et al.  Insulin and atheroma. , 1969, Lancet.

[58]  J. B. Duguid.  Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. , 1946, The Journal of pathology and bacteriology.

[59]  I. Juhan-vague,et al.  Phosphatidylinositol turnover during stimulation of plasminogen activator inhibitor-1 secretion induced by oxidized low density lipoproteins in human endothelial cells. , 1993, Journal of lipid research.

[60]  ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. , 1993, European heart journal.

[61]  J. Loo.  Predictive value of hemostatic variables in cardiovascular disease , 1992 .

[62]  C. Kluft,et al.  Insulin resistance and changes in haemostatic variables , 1992 .

[63]  M. Laakso,et al.  Familial aggregation of non-insulin dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins. , 1991, Atherosclerosis.

[64]  D. Keber,et al.  Plasminogen activator inhibitor I response to a carbohydrate meal in obese subjects , 1990 .

[65]  J. Gris,et al.  Impact of Physical Training on Plasminogen Activator Inhibitor Activity in Sedentary Men , 1990 .

[66]  E. Tremoli,et al.  Atherogenic lipoproteins and release of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells , 1990 .

[67]  P. Deurenberg,et al.  Body composition and weight reduction in relation to antigen and activity of plasminogen activitor inhibitor (PAI-1) in overweight individuals , 1990 .

[68]  A. Meinders,et al.  Acute exogenous hyperinsulinaemia does not result in elevation of plasma plasminogen activator inhibitor-1 (PAI-1) in humans , 1990 .

[69]  B. Bennett,et al.  The activity of plasminogen activator inhibitor-1 (PAI-1) of human platelet , 1990 .

[70]  G. Dahlén,et al.  Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. , 1989, European heart journal.

[71]  R. Stenling,et al.  Reduction of Elevated Plasminogen Activator Inhibitor Levels During Modest Weight Loss , 1989 .

[72]  K. Pyörälà,et al.  Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. , 1979, Diabetes care.

[73]  J. Vague,et al.  The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. , 1956, The American journal of clinical nutrition.