pai-039 and Atherosclerosis

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of fibrinolysis and regulates cell migration and fibrosis. Preclinical studies using genetically altered mice and biological or small molecule inhibitors have elucidated a role for PAI-1 in the pathogenesis of thrombosis, vascular remodeling, renal injury, and initiation of diabetes. Inhibition of PAI-1 is a potential therapeutic strategy in these diseases.

Topics: Animals; Atherosclerosis; Fibrinolysis; Humans; Indoleacetic Acids; Kidney Diseases; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; Thrombosis

Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient (. Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.

Topics: Animals; Atherosclerosis; Cellular Senescence; Diet, Western; Disease Models, Animal; Indoleacetic Acids; Macrophages; Metabolic Syndrome; Mice; Mice, Knockout; Obesity; Plaque, Atherosclerotic; Plasminogen Activator Inhibitor 1; Receptors, LDL