Cardiomyocyte-specific CYP2J2 and its therapeutic implications

ABSTRACT

Introduction

Cytochrome P450s (CYPs) are a superfamily of monooxygenases with diverse biological roles. CYP2J2 is an isozyme highly expressed in the heart where it metabolizes endogenous substrates such as N-3/N-6 polyunsaturated fatty acids (PUFA) to produce lipid mediators involved in homeostasis and cardioprotective responses. Expanding our knowledge of the role CYP2J2 has within the heart is important for understanding its impact on cardiac health and disease.

Areas covered

The objective of this review was to assess the state of knowledge regarding cardiac CYP2J2. A literature search was conducted using PubMed-MEDLINE (from 2022 and earlier) to evaluate relevant studies regarding CYP2J2-mediated cardioprotection, small molecule modulators, effects of CYP2J2 substrates toward biologically relevant effects and implications of CYP2J2 polymorphisms and sexual dimorphism in the heart.

Expert opinion

Cardiac CYP2J2-mediated metabolism of endogenous and exogenous substrates have been shown to impact cardiac function. Identifying individual factors, like sex and age, that affect CYP2J2 require further elucidation to better understand CYP2J2ʹs clinical relevance. Resolving the biological targets and activities of CYP2J2-derived PUFA metabolites will be necessary to safely target CYP2J2 and design novel analogues. Targeting CYP2J2 for therapeutic aims offers a potential novel approach to regulating cardiac homeostasis, drug metabolism and cardioprotection.

KEYWORDS:

• Cytochrome P450
• CYP2J2
• cardiomyocyte
• eicosanoids
• epoxides
• heart disease
• metabolism
• pharmacogenetics
• polyunsaturated fatty acids
• xenobiotics

Article highlights

• Cytochrome P450 epoxygenase (CYP)2J2 is highly expressed in the heart and mediates metabolism of numerous endogenous and exogenous substrates.

• Cardiac CYP2J2-mediated metabolism of N-3/N-6 PUFA generates lipid mediators involved in homeostasis and cardioprotective responses.

• CYP2J2 demonstrates differing effects in various disease states such as cardiac disease versus cancer.

• CYP2J2 polymorphisms have potential clinically relevant consequences.

• Direct pharmacological inhibitors or activators of CYP2J2 are potential novel therapeutic agents.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by a grant from the National Sciences and Engineering Research Council of Canada (NSERC) RGPIN-2018-05696 to JM Seubert.