Abstract 14461: How Does Perhexiline Modulate Myocardial Energetics and Ameliorate Redox Stress?
Introduction: Perhexiline (Perhx) exerts anti-ischemic effects via mechanisms that may include: 1) inhibition of myocardial carnitine palmitoyl transferases, and associated substrate shift with consequent improved cardiac energetic status; and 2) potentiation of nitric oxide responsiveness. The CASPER was a randomized, placebo-controlled trial of the effect of Perhx on perioperative hemodynamic changes in patients undergoing non-emergent CABG. In a subset of these patients, we evaluated effects of Perhx on 1) the anti-oxidant thioredoxin (TRX) system, including TRX-1, Trx reductase (TRX-R), and thioredoxin-interacting protein (TXNIP), the physiological antagonist of TRX; 2) eNOS, and peNOS (Ser1177); 3) the energetic sensor AMPK, and its downstream effector PGC-1alpha.
Methods: Left ventricular biopsies were obtained from n=24 patients (n=12 in each treatment arm) at 3 stages during the operation: before aortic cross-clamping (pre-ischemia), immediately prior to cross clamp release (end-ischemia), and 10 mins after release of the cross-clamp (reperfusion). The biopsies were mechanically lysed in liquid nitrogen and dissolved in lysis buffer. Expressions of the following proteins were analysed using Western blot analysis: TRX-1, TXNIP, TRX-R, eNOS, peNOS, AMPK, pAMPK alpha (Thr172),and PGC-1alpha. Two-way ANOVA was used to compare differential protein expressions between Perhx versus placebo at the three timepoints of ischaemia-reperfusion.
Results: None of the parameters changed significantly between biopsy periods. There was a significant decrease in TXNIP expression in the perhx treated group versus placebo (p<0.001). While there was a non significant reduction in TRX-R (p=0.07) by Perhx, TRX-1 expressions did not differ. Expressions of eNOS and peNOS (Ser1177) did not change with Perhx treatment. There was a significant increase in AMPK expressions (p=0.03), and PGC-1 alpha (p=0.03); pAMPK alpha (Thr172) expressions did not change with Perhx treatment.
Conclusions: Perhexiline, in addition to its previously described effects: 1) suppresses expression of TXNIP, and 2) increases expression of AMPK and PGC-1 alpha. These effects may contribute to the beneficial effects of Perhx on redox stress and energetic impairment.
- © 2011 by American Heart Association, Inc.