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Journal of Pharmacology and Experimental Therapeutics

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OtherCardiovascular

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

Xiao-Han Tang, Jessica Gambardella, Stanislovas S. Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 13, 2021, JPET-AR-2021-000806; DOI: https://doi.org/10.1124/jpet.121.000806
Xiao-Han Tang
1Weill Cornell Medicine, United States
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Jessica Gambardella
22 Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, United States
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Stanislovas S. Jankauskas
3Einstein Med Coll, United States
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Xujun Wang
22 Departments of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, United States
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Gaetano Santulli
4Department of Medicine (Cardiology) and Molecular Pharmacology, Albert Einstein College of Medicine, United States
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Lorraine J. Gudas
5Dept. of Pharmacology, Cornell University Medical College, United States
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Roberto Levi
6Department of Pharmacology, Weill Cornell Medicine, United States
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  • For correspondence: rlevi@med.cornell.edu
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Abstract

We previously demonstrated that the selective retinoic acid β2-receptor (RARβ2) 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 decline in 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 SOD2 and ANGPTL4 transcriptional levels as well as the increase in NOX-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 regulating a set of genes responsible for decreasing oxidative stress and ROS production. 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 We previously published that the selective retinoic acid β2-receptor (RARβ2) agonist AC261066 reduces oxidative stress in an ex-vivo murine model of ischemia/reperfusion. We report here that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF), by regulating a set of genes responsible for decreasing oxidative stress and consequent fibrogenesis. Since myocardial infarction is a recognized major cause of HF, our data identify RARβ2 as a potential pharmacological target in the treatment of HF.

  • congestive heart failure
  • retinoids
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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OtherCardiovascular

RARβ2 as a potential HF treatment target

Xiao-Han Tang, Jessica Gambardella, Stanislovas S. Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 13, 2021, JPET-AR-2021-000806; DOI: https://doi.org/10.1124/jpet.121.000806

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OtherCardiovascular

RARβ2 as a potential HF treatment target

Xiao-Han Tang, Jessica Gambardella, Stanislovas S. Jankauskas, Xujun Wang, Gaetano Santulli, Lorraine J. Gudas and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics August 13, 2021, JPET-AR-2021-000806; DOI: https://doi.org/10.1124/jpet.121.000806
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