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 journalArticle

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 (US)
Pages (from-to)642-651
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume371
Issue number3
DOIs
StatePublished - Jan 1 2019

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Therapeutic Uses
Heart Failure
Oxidative Stress
Hemodynamics
CREB-Binding Protein
Glutamate-Cysteine Ligase
Heme Oxygenase-1
NF-kappa B
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Cardiac Output
Stroke Volume
Catalase
Infarction
Heart Ventricles
Rodentia
Catalytic Domain
Esters
Pharmacology
Blood Pressure
Inflammation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Therapeutic effects of Nrf2 activation by bardoxolone methyl in chronic heart failure. / Tian, Changhai; Gao, Lie; Zhang, Andi; Hackfort, Bryan T.; Zucker, Irving H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 371, No. 3, 01.01.2019, p. 642-651.

Research output: Contribution to journalArticle

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