In the vessel lumen, PAI-1, a primary physiologic inhibitor of plasminogen activators, both tissue and urokinase type, is critical in the thrombolytic response to vascular injury. Increased PAI-1 diminishes the fibrinolytic response and consequently a larger thrombus burden and a greater risk of thrombotic occlusion is expected. Further, persistence of thrombi can accelerate the process of atherosclerosis by exposing the vessel wall to clot-associated mitogens. Paradoxically, this decrease in SMC migration may actually potentiate the genesis of vulnerable plaques. Limiting SMC migration into the neointima and the cap overlying plaques may lead to the formation of more thin, acellular fibrous caps as opposed to more cellular caps.
Acellular caps are more prone to rupture.
This increased expression of PAI-1 is associated with a diminished fibrinolytic response. By contrast, the infusion of insulin and glucose with the use of euglycemic clamp techniques led to a decrease in the concentration of free fatty acid, while the concentration of triglycerides remained low throughout the infusion. These experiments strongly support that an interaction between lipids, particularly triglycerides and free fatty acids, glucose, and insulin modulates expression of PAI-1 in diabetic subjects. Combining insulin and free fatty acids resulted in a synergistic increase in the expression of PAI-1. The molecular mechanisms by which insulin alters expression of PAI-1 was characterized in HepG2 cells.