Abstract 12241: Pharmacological Inhibition of PAI-1 Rescues the Defect in Ischemia-Induced Neovasculature in Type II Diabetic Mice
Background: Type II diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with DM. However, the role of PAI-1 in the development of DM-associated vascular disease is poorly defined.
Methods and Results: Hind-limb ischemia was generated by femoral artery occlusion in diet-induced diabetic mice and age-matched normal chow (NC)-fed mice. Plasma was analyzed for glucose, non-esterified fatty acids, and PAI-1. PAI-039, a specific, small molecule pharmacological inhibitor of PAI-1, was orally administered to mice (1 mg/kg, twice daily for 14 days) to determine if PAI-1 attenuates neovasculature formation in DM mice. PAI-1 activity and antigen were significantly increased within 2 weeks of DM onset and remained elevated throughout the experimental period. PAI-039 normalizes elevated plasma PAI-1 activity in the DM group. Color Laser Doppler showed that the blood flow perfusion in ischemic hind-limb was significantly decreased in the DM nontreated group compared to NC nontreated group at 5, 7, and 14 days (n = 6/group, P ≤ 0.05). Decreased blood flow in the DM group correlated to decreased density of CD31-positive vessels in ischemic muscle compared with the NC tissue. Pharmacologic inhibition of PAI-1 with PAI-039 rescued the ischemia-mediated impairments in blood flow perfusion and vessel density in ischemic muscles in DM group compared to vehicle-DM group (n = 6/group, P ≤ 0.05).
Conclusions: Taken together, these findings illustrate that the pharmacologic inhibition of elevated PAI-1 rescues the impairments in ischemia-mediated flow perfusion and neovasculature observed in DM, and may have efficacy as a therapeutic strategy to prevent diabetic microangiopathy.
- © 2013 by American Heart Association, Inc.