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Research ArticleCardiovascular

A Retinoic Acid Receptor β2 Agonist Improves Cardiac Function in a Heart Failure Model

Xiao-Han Tang, Jessica Gambardella, Stanislovas Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics November 2021, 379 (2) 182-190; DOI: https://doi.org/10.1124/jpet.121.000806
Xiao-Han Tang
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Jessica Gambardella
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Stanislovas Jankauskas
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Xujun Wang
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Gaetano Santulli
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Lorraine J. Gudas
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Roberto Levi
Department of Pharmacology, Weill Cornell Medicine, New York, New York (X.-H.T., L.J.G., R.L.); Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (J.G., S.J., X.W., G.S.)
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Abstract

We previously demonstrated that the selective retinoic acid receptor (RAR) β2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α-smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RARβ2 as a potential pharmacological target in the treatment of HF.

SIGNIFICANCE STATEMENT A previous report showed that the selective retinoic acid receptor (RAR) β2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RARβ2 as a potential pharmacological target in the treatment of HF.

Footnotes

    • Received June 22, 2021.
    • Accepted August 10, 2021.
  • ↵1 X.-H.T. and J.G. contributed equally to this work as co-first authors.

  • This research was supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK113088 to L.J.G.] and Weill Cornell funds (to R.L.). The Santulli Laboratory was supported in part by the NIH NIDDK [Grants R01-DK123259, R01-DK033823, R00-DK107895], National Heart, Lung, and Blood Institute [Grants R01-HL146691, R01-HL159062, T32-HL144456], and National Institute on Aging [Grant R56-AG066431] (all to G.S.); by the Irma T. Hirschl and Monique Weill-Caulier Trusts (to G.S.), and by the American Heart Association [Grants AHA-20POST35211151 to J.G. and AHA-21POST836407 to S.S.J.].

  • https://doi.org/10.1124/jpet.121.000806.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 379 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 379, Issue 2
1 Nov 2021
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Research ArticleCardiovascular

Tang et al.

Xiao-Han Tang, Jessica Gambardella, Stanislovas Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics November 1, 2021, 379 (2) 182-190; DOI: https://doi.org/10.1124/jpet.121.000806

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Research ArticleCardiovascular

Tang et al.

Xiao-Han Tang, Jessica Gambardella, Stanislovas Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics November 1, 2021, 379 (2) 182-190; DOI: https://doi.org/10.1124/jpet.121.000806
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