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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1438567
This article is part of the Research Topic Cytochrome P450s, Their Modulators, and Metabolites in Cardiovascular Function and Disease View all articles

1-Hydroxyeicosatetraenoics Induces Cellular Hypertrophy in an Enantioselective Manner

Provisionally accepted
Sara A. Helal Sara A. Helal 1,2Ahmed A. El-Sherbeni Ahmed A. El-Sherbeni 3Ayman O. El-Kadi Ayman O. El-Kadi 1*
  • 1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
  • 2 Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt
  • 3 Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt

The final, formatted version of the article will be published soon.

    Background: R/S enantiomers of 11-hydroxyeicosatertraenoic acid (11-HETE) are formed from arachidonic acid by enzymatic and non-enzymatic pathways. 11-HETE is predominately formed by the cytochrome P450 1B1 (CYP1B1). The role of CYP1B1 in the development of cardiovascular diseases is well established.Objectives: This study aimed to assess the cellular hypertrophic effect of 11-HETE enantiomers in human RL-14 cardiomyocyte cell line and examine their association with CYP1B1 levels.Methods: Human fetal ventricular cardiomyocyte, RL-14 cells, were treated with 20 µM (R) or (S) 11-HETE for 24 h. Thereafter, cellular hypertrophic markers and cell size were then determined using real-time polymerase chain reaction (RT-PCR) and phase-contrast imaging, respectively. The mRNA and protein levels of selected CYPs were determined using RT-PCR and Western blot, respectively. In addition, we examined the effect of (R) and (S) 11-HETE on CYP1B1 catalytic activity using human recombinant CYP1B1 and human liver microsomes.Results: Both (R) and (S) 11-HETE induced cellular hypertrophic markers and cell surface area in RL-14 cells. Both enantiomers significantly upregulated CYP1B1, CYP1A1, CYP4F2, and CYP4A11 at the mRNA and protein levels, however, the effect of the S-enantiomer was more pronounced. Furthermore, 11(S)-HETE increased the mRNA and protein levels of CYP2J and CYP4F2, whereas 11(R)-HETE increased only CYP4F2. Only 11(S)-HETE significantly increased the catalytic activity of CYP1B1 in recombinant human CYP1B1, suggesting allosteric activation in an enantioselective manner.Our study provides the first evidence that 11-HETE can induce cellular hypertrophy in RL-14 cells via the increase in CYP1B1 mRNA, protein, and activity.

    Keywords: Arachidonic Acid, cytochrome P450, Hydroxyeicosatertraenoic acid, Cellular hypertrophy, enantiomers

    Received: 26 May 2024; Accepted: 08 Jul 2024.

    Copyright: © 2024 Helal, El-Sherbeni and El-Kadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ayman O. El-Kadi, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2R3, Alberta, Canada

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.