Abstract 15540: NRF2 Upregulation Attenuates Post-Infarct Ventricular Remodeling by Modifying Redox Signalling
Background: Adverse remodeling following myocardial infarction (MI) contributes to substantial morbidity, including heart failure and arrhythmia. Reactive oxygen species (ROS) play an important role in triggering molecular signalling events that drive remodeling post MI and reperfusion. The novel synthetic triterpenoid, bardoxolone methyl, is a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling as it upregulates cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. We hypothesized that Nrf2 activation by dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, may improve post-infarct remodeling.
Methods/Results: DH404, administered orally in rats from day 2 post MI (30 min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 by left ventricular end-systolic area (sham 0.14±0.01 cm2, MI vehicle 0.29±0.04 cm2 vs. MI DH404 0.18±0.02 cm2, P<0.05) and infarct size (21.3±3.4 % MI vehicle vs. 10.9±2.3 % MI DH404, P<0.05). This was associated with improved systolic function (fractional shortening: sham 71.9±2.6%, MI vehicle 36.2±1.9% vs. MI DH404 58.6±4.0%, P<0.05). These structural and functional benefits were associated with lower myocardial expression of atrial natriuretic peptide and fibronectin (both P<0.01 vs. MI vehicle) in DH404-treated MI rats. MI resulted in increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro - a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide bioavailability - which was ameliorated by DH404. Parallel experiments in cultured cardiomyocytes suggested that the decrease in glutathionylated eNOS is mediated by an increase in functional interaction with the deglutathionylating enzyme glutaredoxin 1 (Grx1).
Conclusion: The bardoxolone derivative DH404 significantly attenuated cardiac remodeling post MI, at least in part, by re-coupling of eNOS and increasing the functional interaction of Grx1 with eNOS. This agent may have clinical benefits protecting against post MI cardiomyopathy.
Author Disclosures: K.J. Bubb: None. C. Kok: None. O. Tang: None. N.B. Rasko: None. T. Hansen: None. R. Ritchie: None. R. Bhindi: None. S.A. Reisman: Employment; Significant; employed by reata. C. Meyer: Employment; Significant; Reata Pharmaceuticals inc. K. Ward: Employment; Significant; Reata Pharmaceuticals inc.. K. Karimi Galougahi: None. G. Figtree: None.
- © 2016 by American Heart Association, Inc.