fibrin and Insulin-Resistance

Fibrinogen is a protein synthesised by the liver. It is converted by thrombin to an insoluble fibrin network to induce, together with platelet aggregates, haemostasis in response to rupture of endothelium. This change includes several steps and implied factor XIII. Molecular properties of fibrin are responsible for its important role in hemostasis which goes beyond the one of a simple final inert product of coagulation. In fact, fibrin regulates thrombin and factor XIII activities and its own destruction also called fibrinolysis. The multiple domains of fibrinogen and fibrin confer a role not only in haemostasis but also in wound healing, cellular migration and proliferation, due to interactions with endothelial cells, leukocytes and components of the extracellular matrix. Fibrin must be removed once its haemostatic role has been reached. The fibrinolytic process takes place in the vessel lumen. It is strongly regulated by the plasma concentration of an inhibitor called plasminogen activator inhibitor-1 (PAI-1) which synthesis strongly increases in obese insulin resistant and diabetic patients. Data from animal models show that increased PAI-1 production represents a prothrombotic state. Fibrinolysis plays also a role in tissue remodeling (vascular wall, placenta, adipose tissue....) by degrading the extracellular matrix, by activating growth factors or modifying cellular adhesion and migration properties. It has been proposed that PAI-1 in excess could be directly responsible for the development of atherothrombosis in insulin resistant subjects. Moreover recent results from transgenic mice indicate that PAI-1 in excess interferes also with weight gain. These data point out the importance of the haemostatic system in the extra vascular phenomenon of tissue remodeling.

Topics: Animals; Arteriosclerosis; Carboxypeptidase B2; Cell Movement; Diabetes Mellitus; Disease Models, Animal; Endothelial Cells; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Insulin Resistance; Metalloproteases; Mice; Mice, Transgenic; Plasminogen Activator Inhibitor 1; Risk Factors; Thrombin; Thrombosis; Wound Healing

Topics: Coronary Disease; Fibrin; Fibrinolysis; Humans; Insulin Resistance; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Risk Factors; Tissue Plasminogen Activator

Topics: Arteriosclerosis; Fibrin; Fibrinolysis; Humans; Hyperinsulinism; Insulin Resistance; Plasminogen Inactivators; Thrombosis; Tissue Plasminogen Activator

Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase (MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin-resistant diabetic rat hearts.. By immunohistochemistry and in situ hybridization, transforming growth factor-beta1 (TGF-beta1) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor-1 (PAI-1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP-2 and decreased expression of membrane type-1 MMP (MT1-MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining.. In addition to upregulation of PAI-1, downregulation of MMP-2 and MT1-MMP might play a crucial role in coronary matrix remodeling in insulin-resistant diabetes. These molecules appear to be regulated by angiotensin II via stimulation of TGF-beta1.

Topics: Angiotensin II; Animals; Collagen Type I; Collagen Type III; Coronary Vessels; Diabetes Mellitus, Type 2; Down-Regulation; Fibrin; Fibrosis; Insulin Resistance; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Rats; Rats, Inbred OLETF; Receptor, Melatonin, MT1; Transforming Growth Factor beta