Abstract 19468: Pharmacological Inhibition of Plasminogen Activator Inhibitor-1 Decreases Atherosclerosis Formation in a Murine Model of Obesity and Metabolic Syndrome
Introduction: Metabolic syndrome (MetS=abdominal obesity, dyslipidemia, hyperglycemia, and hypertension) is strongly associated with increased risk of atherosclerosis (athero) and increased expression of plasminogen activator inhibitor-1 (PAI-1), a major regulator of fibrinolysis and cell migration. However, whether PAI-1 promotes athero in MetSyn, or is simply an associated marker, is unknown.
Methods and Results: We fed LDL receptor-deficient mice Western diet (WD) to induce obesity, MetS, and athero. PAI039 group (n=8) received WD with PAI039 (5 mg PAI-039/g chow), a highly-specific inhibitor of PAI-1. Control group (n=8) received WD. After 12 wks, 3 mice in each group were euthanized. Macrophage (MP) content in epididymal white adipose tissue was significantly lower in PAI039-treated mice vs. controls. Aortic root athero plaque area was 122±23 μm2 in PAI039-treated mice vs. 272±62 μm2 in controls (P=0.12). After 24 wks, remaining 10 animals were euthanized. Aortic root, arch, and descending thoracic aortic athero was significantly reduced in PAI039-treated mice vs. controls (P<0.05; n=5/group). Plasma total cholesterol concentration did not differ significantly between groups. PAI039 treatment produced durable protection against obesity (after 24 wks of WD, body weights were 37±2 g and 47±2 g in PAI039-treated and control mice, respectively; P<0.05; n=5/group) without any significant effect on chow consumption. PAI039 also significantly reduced hyperglycemia, assessed by plasma hemoglobin A1c (6.5±0.8% in PAI-039 group vs. 8.1±0.5% in controls; P<0.05; n=5/group). In vitro experiments revealed that PAI039 significantly inhibited migration of wild-type smooth muscle cells (SMCs) and MPs, but had no anti-migratory effect on cells from PAI-1-deficient mice.
Conclusions: PAI039, an inhibitor of PAI-1, inhibits athero in a model of WD-induced obesity and MetS. PAI039 also inhibits key processes recognized to promote athero, including visceral adipose tissue inflammation, glucose intolerance, and migration of MPs and SMCs. Together, these results suggest that 1) PAI-1 is an important driver of athero in MetS, and 2) pharmacological inhibition of PAI-1 may be a useful strategy to prevent vascular complications of obesity and MetS.
Author Disclosures: Y. Ji: None. T.L. Strawn: None. W.P. Fay: None.
- © 2016 by American Heart Association, Inc.