Therapeutic effects of Nrf2 activation by bardoxolone methyl in chronic heart failure

Changhai Tian, Lie Gao, Andi Zhang, Bryan T. Hackfort, Irving H. Zucker

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Oxidative stress plays an important role in the pathogenesis of chronic heart failure (CHF) in many tissues. Increasing evidence suggests that systemic activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling can protect against postinfarct cardiac remodeling by reducing oxidative stress. However, it remains to be elucidated if Nrf2 activation exerts therapeutic effects in the CHF state. Here, we investigated the beneficial hemodynamic effects of bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me), a pharmacological activator of Nrf2, in a rodent model of CHF. Based on echocardiographic analysis, rats at 12 weeks post–myocardial infarction (MI) were randomly split into four groups. CDDO-Me (5 mg/kg, i.p.) was administered daily for another 2 weeks in sham and CHF rats and compared with vehicle treatment. Echocardiographic and hemodynamic analysis suggest that short-term CDDO-Me administration increased stroke volume and cardiac output in CHF rats and decreased left ventricle end-diastolic pressure. Molecular studies revealed that CDDO-Me–induced cardiac functional improvement was attributed to an increase of both Nrf2 transcription and translation, and a decrease of oxidative stress in the noninfarcted areas of the heart. Furthermore, CDDO-Me reduced NF-kB binding and increased Nrf2 binding to the CREB-binding protein, which may contribute to the selective increase of Nrf2 downstream targets, including NADPH Oxidase Quinone 1, Heme Oxygenase 1, Catalase, and Glutamate-Cysteine Ligase Catalytic Subunit, and the attenuation of myocardial inflammation in CHF rats. Our findings suggest that Nrf2 activation may provide beneficial cardiac effects in MI-mediated CHF.

Original languageEnglish
Pages (from-to)642-651
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume371
Issue number3
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant P01HL62222 (I.H.Z.)], the American Heart Association Career Development Award [19CDA34520004 (C.T.)], and the Undergraduate Summer Research Fellowship program through the American Physiological Society (A.Z.).

Funding Information:
ABBREVIATIONS: ARE, antioxidant response element; CBP, CREB-binding protein; CDDO-Me, bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester ); CHF, chronic heart failure; DH404, dihydro-CDDO-trifluoroethyl amide; eNOS, endothelial nitric oxide synthase; Grx1, Glutaredoxin-1; HO-1, Heme Oxygenase 1; LVEDP, left ventricle end-diastolic pressure; MI, myocardial infarction; NIH, National Institutes of Health; NQO1, NADPH Oxidase Quinone 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; Veh, vehicle.

Funding Information:
All animal studies were carried out with the approval of the University of Nebraska Medical Center Institutional Animal Care and Use Committee and followed the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals.

Funding Information:
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant P01HL62222 (I.H.Z.)], the American Heart Association Career Development Award [19CDA34520004 (C.T.)], and the Undergraduate Summer Research Fellowship program through the American Physiological Society (A.Z.). The authors have no conflict of interest. https://doi.org/10.1124/jpet.119.261792. s This article has supplemental material available at jpet.aspetjournals.org.

Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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