Kristen J Bubb1, Cindy Kok1, Owen Tang1, Nathalie B Rasko1, Asa B Birgisdottir2, Thomas Hansen1, Rebecca Ritchie3, Ravinay Bhindi4, Scott A Reisman5, Colin Meyer5, Keith Ward5, Keyvan Karimi Galougahi1, Gemma A Figtree6. 1. North Shore Heart Research Group, Kolling Institute, University of Sydney and Royal North Shore Hospital, Sydney, Australia. 2. North Shore Heart Research Group, Kolling Institute, University of Sydney and Royal North Shore Hospital, Sydney, Australia; Department of Cardiothoracic and Vascular Surgery, Heart and Lung Clinic, University Hospital of North Norway, Tromsø, Norway. 3. Baker IDI Heart and Diabetes Institute, Melbourne, Australia. 4. North Shore Heart Research Group, Kolling Institute, University of Sydney and Royal North Shore Hospital, Sydney, Australia; Department of Cardiology, Royal North Shore Hospital and University of Sydney, Australia. 5. Reata Pharmaceuticals, Inc. Irving, TX, USA. 6. North Shore Heart Research Group, Kolling Institute, University of Sydney and Royal North Shore Hospital, Sydney, Australia; Department of Cardiology, Royal North Shore Hospital and University of Sydney, Australia. Electronic address: gemma.figtree@sydney.edu.au.
Abstract
BACKGROUND: The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post-infarct cardiac remodeling in rats. METHODS/ RESULTS: DH404, administered from day 2 post myocardial infarction (MI: 30min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end-systolic area: sham 0.14±0.01cm2, MI vehicle 0.29±0.04cm2 vs. MI DH404 0.18±0.02cm2, P<0.05); infarct size (21.3±3.4% MI vehicle vs. 10.9±2.3% MI DH404, P<0.05) with associated benefits on 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 (ANP, P<0.01 vs. MI vehicle), and decreased fibronectin (P<0.01 vs. MI vehicle) in DH404-treated MI rats at 28 days. MI increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro - a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide (NO) bioavailability. MI-induced eNOS glutathionylation was substantially ameliorated by DH404. An associated increase in glutaredoxin 1 (Grx1) co-immunoprecipitation with eNOS without a change in expression was mechanistically intriguing. Indeed, in parallel in vitro experiments, silencing of Grx1 abolished the protective effect of DH404 against Angiotensin II-induced eNOS uncoupling. 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.
BACKGROUND: The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post-infarct cardiac remodeling in rats. METHODS/ RESULTS:DH404, administered from day 2 post myocardial infarction (MI: 30min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end-systolic area: sham 0.14±0.01cm2, MI vehicle 0.29±0.04cm2 vs. MI DH404 0.18±0.02cm2, P<0.05); infarct size (21.3±3.4% MI vehicle vs. 10.9±2.3% MI DH404, P<0.05) with associated benefits on 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 (ANP, P<0.01 vs. MI vehicle), and decreased fibronectin (P<0.01 vs. MI vehicle) in DH404-treated MI rats at 28 days. MI increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro - a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide (NO) bioavailability. MI-induced eNOS glutathionylation was substantially ameliorated by DH404. An associated increase in glutaredoxin 1 (Grx1) co-immunoprecipitation with eNOS without a change in expression was mechanistically intriguing. Indeed, in parallel in vitro experiments, silencing of Grx1 abolished the protective effect of DH404 against Angiotensin II-induced eNOS uncoupling. 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.
Authors: Andrey Kazakov; Rabea A Hall; Christian Werner; Timo Meier; André Trouvain; Svetlana Rodionycheva; Alexander Nickel; Frank Lammert; Christoph Maack; Michael Böhm; Ulrich Laufs Journal: Basic Res Cardiol Date: 2018-09-06 Impact factor: 17.165