Abstract 16852: Inhibition of Hypoxia-Inducible Factor Prolyl Hydroxylase Reduces Infarct Size and Improves Cardiac Function in a Rat Model of Myocardial Ischemia Reperfusion Injury
Hypoxia-inducible factor (HIF) has been shown to have cardioprotective effects when stabilized prior to a cardiac ischemic event. In the present studies, we investigated the cardioprotective effects of HIF stabilization post-ischemia, at the time of reperfusion, using the HIF prolyl-hydroxylase inhibitor (HIF-PHI) FG-6515. In a first study, the left coronary artery was temporarily ligated in rats to induce myocardial infarction (MI). After 30 minutes of ischemia, the ligature was removed, the myocardium was reperfused and FG-6515 (2, 6 or 20 mg/kg) or vehicle was administered once intravenously. Twenty-four hours after reperfusion, heart sections were stained with triphenyl tetrazolium chloride to measure infarct size as a percentage of the area at risk (AAR). FG-6515 given at reperfusion significantly decreased infarct size in a dose dependent manner (Table 1) and induced non-significant decreases in serum cardiac troponin I. In a second study using the same MI procedure, FG-6515 (20 mg/kg) was administered either once at reperfusion or 3 times (at reperfusion, 24 and 48 hours post-reperfusion). In addition, an MI group and a sham group received vehicle. Twenty-eight days after reperfusion, a Millar catheter was inserted in the left ventricle to measure cardiac function. FG-6515 significantly improved ejection fraction (EF), end-systolic volume (ESV) and relaxation time constant (RT). Three administrations of FG-6515 at daily intervals for the first 48 hours after reperfusion were more efficacious than a single administration (Table 2). In conclusion, these data support the use of HIF-PHI at reperfusion to limit infarct size and improve cardiac function after MI.
- © 2011 by American Heart Association, Inc.