Cytochrome P450s, Their Modulators, and Metabolites in Cardiovascular Function and Disease

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Background

Cytochrome P450 enzymes (CYPs) mediate the oxidative metabolism of endogenous molecules and xenobiotics. CYPs are differentially expressed, can be induced in various organs/cell types, and affect the efficacy and toxicity of drugs in a tissue specific manner. In the cardiovascular system (CS), certain CYP members (e.g., CYP2J2, CYP4A11, CYP2C8) are expressed in cardiomyocytes, vascular, stromal and immune cells. The complexity of various CYP isoforms and polymorphisms, their metabolic products, and therapeutic potential make CYP research challenging and of vital interest. Various research groups have contributed to identifying CYP expression and relative abundance in the CS. Such contributions have improved our understanding of drug-drug interactions in cardiovascular disease (CD) treatment and helped identify cardioprotective CYPs (e.g., CYP2J2). Also, major contributions have been made on the roles of CYP-derived polyunsaturated fatty acid metabolites in cardiovascular function. Identification of the various CYP-derived PUFA metabolites, their receptors, and roles in CD are of current interest for drug discovery efforts.

Current research suggests that cytochrome P450 enzymes, their modulators, and metabolites (CYP pathway) contribute to cardiovascular homeostasis and disease through various mechanisms including reprogramming cellular response to endogenous and exogenous agents. However, significant deficiencies remain in our understanding of the precise metabolites, pathway(s), and signaling cross-talks responsible for the effects of CYP pathway in cardiovascular function. These deficiencies may be responsible for the dearth in successful clinical translation of key findings in the field. It is hoped that this Research Topic would provide novel research data and perspectives on the mechanisms and roles of the CYP pathway in cardiovascular homeostasis and disease that would close some of the gaps in our understanding and lead to new research directions. Of importance to achieving this goal is the identification of pathways activated downstream of the CYP pathway. For example, the recent identification of GPR75 as a receptor for the CYP4A/F family arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), provides new direction in studying this pathway in hypertension, ischemic heart disease, and heart failure. Further, associations of CYP4A/F and GPR75 variants with diabetes and obesity in humans identifies patients that could benefit from targeting these pathways.

The scope of this Research Topic includes novel original research articles, perspectives, and reviews on:

1. Receptors and pathways activated by CYP450 metabolites. Contributions should focus on endogenous and xenobiotic metabolites involved in cardiovascular function and disease. Novel mechanism of action of CYP450 metabolites will also be included.

2. Regulation of CYP450 in cardiovascular disease (CD) and treatment. Contributions should include transcriptional and post-transcriptional regulation of CYP450.

3. Preventive and therapeutic applications of CYP450 modulators and met

Keywords: Cytochrome P450, polyunsaturated fatty acids, epoxyeicosatrienoic acid, hydroxyeicosatetraenoic acid, cardiomyocyte, endothelium, ischemia, mitochondria, xenobiotics, heart failure, vascular tone, vascular smooth muscle, obesity, diabetes, remodeling, hyp

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