Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic

Background-Obesity and insulin resistance are associated with accelerated m acrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activato r inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinol ysis. Methods and Results-To determine whether hypofibrinolysis in blood and tiss ues and its potential sequelae could be attenuated pharmacologically, we st udied genetically modified obese mice. By 10 weeks of age, obese mice exhib ited increases in left ventricular weight and glucose and immunoreactive in sulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lea n controls widened by 20 weeks of age. Perivascular fibrosis in coronary ar terioles and small coronary arteries was evident in obese mice 10 and 20 we eks of age, paralleling increases in PAI-1 and tissue factor expression evi dent by immunohistochemical image analysis, in situ hybridization, and reve rse transcription-polymerase chain reaction. Inhibition of ACE activity ini tiated in obese mice 10 weeks of age and continued for 20 weeks arrested th e increase in PAI-1 activity in blood and in cardiac PAI-I and tissue facto r mRNA as well as coronary perivascular fibrosis. Conclusions-Thus, inhibition of proteo(fibrino)lysis and augmented tissue f actor expression in the heart precede and may contribute to the coronary pe rivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.