Targeting Plasminogen activator inhibitor-1 in thrombotic and fibrotic disease

Plasminogen activator inhibitor-1 (PAI-1) is the physiologic inhibitor of both tissue and urokinase plasminogen activator (tPA and uPA, respectively). Numerous studies over the last two decades have demonstrated PAI-1's role in normal physiologic processes, such as thrombolysis and wound healing. PAI-1 has also been associated with many disease processes, including acute diseases such as sepsis and myocardial infarction, and chronic disorders such as cancer, atherosclerosis, type 2 diabetes and fibrotic disease of the lung, kidney, and heart. The association of PAI-1 with these syndromes has led to the suggestion that PAI-1 may contribute directly to pathology, and that inhibition of PAI-1 may be an effective approach to treating a wide variety of diseases, especially diseases where fibrosis is a significant component. PAI-1 expression is also directly linked to obesity, and insulin resistance, which are known to be primary drivers of fibrotic disease. PAI-1 is synthesized in adipocytes, and there is a strong correlation between body mass index (BMI) and plasma levels of PAI-1 in humans. In genetically obese and diabetic mice, PAI-1 deficiency protects against weight gain and improves metabolic profiles. In nutritionally-induced obesity, insulin resistance is dramatically attenuated in mice deficient in PAI-1, and in mice treated with a PAI-1 inhibitor. These observations suggest that PAI-1 may play a direct role in the development of obesity and thereby indirectly in the development of type 2 diabetes. PAI-1 can positively regulate adipose tissue development, which in turn will increase PAI-1 expression. Such a relationship could constitute a positive feedback loop promoting further adipose tissue expansion. Given the association between obesity, type 2 diabetes, and renal fibrosis discussed above, as well as with other fibrotic diseases, these data support the potential of targeting PAI-1 for therapeutic benefit. Based on these observations and on our significant experience with PAI-1 structure/function and its biology this project is identifying and testing PAI-1 antagonist for treatment of thrombotic and fibrotic disease. 

Copyright 2015