Altered Protein Expression of Cardiac CYP2J and Hepatic CYP2C, CYP4A, and CYP4F in a Mouse Model of Type II Diabetes-A Link in the Onset and Development of Cardiovascular Disease?

Benoit Drolet,Carolanne Gélinas,Audrey Blais-Boilard,Alida-Douce Kamaliza,Dany Patoine,Chantale Simard,Sylvie Pilote,Jessica Virgili

doi:10.3390/pharmaceutics9040044

Benoit Drolet, Carolanne Gélinas + Show 6 more

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https://doi.org/10.3390/pharmaceutics9040044

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Abstract

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse model of Type II diabetes (C57BLKS/J-db/db) was used. After sacrifice, livers and hearts were collected, washed, and snap frozen. Total proteins were extracted. Western blots were performed to assess cardiac CYP2J and hepatic CYP2C, CYP4A, and CYP4F protein expression, respectively. Significant decreases in relative protein expression of cardiac CYP2J and hepatic CYP2C were observed in Type II diabetes animals compared to controls (CYP2J: 0.80 ± 0.03 vs. 1.05 ± 0.06, n = 20, p < 0.001); (CYP2C: 1.56 ± 0.17 vs. 2.21 ± 0.19, n = 19, p < 0.01). In contrast, significant increases in relative protein expression of both hepatic CYP4A and CYP4F were noted in Type II diabetes mice compared to controls (CYP4A: 1.06 ± 0.09 vs. 0.18 ± 0.01, n = 19, p < 0.001); (CYP4F: 2.53 ± 0.22 vs. 1.10 ± 0.07, n = 19, p < 0.001). These alterations induced by Type II diabetes in the endogenous pathway (CYP450) of arachidonic acid metabolism may increase the risk for cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2J/CYP2C-generated) and cardiotoxic (CYP4A/CYP4F-generated) metabolites of arachidonic acid.

Highlights

Arachidonic acid (AA) is an essential polyunsaturated fatty acid notably found in cell membrane phospholipids
Many clinical features of human Type II diabetes were shown to be present in the db/db mice (T2D) at sacrifice: severe obesity, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia; confirming the validity of this T2D animal model
The pathophysiology of cardiovascular disease (CVD) is highly complex, and a constellation of risk factors contribute to its development and progression

Summary

Introduction

Arachidonic acid (AA) is an essential polyunsaturated fatty acid notably found in cell membrane phospholipids. The released non-esterified AA acts as a substrate for oxidation by cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP450) enzymes in the heart and elsewhere, thereby generating a cascade of lipid second messengers, orchestrating a broad range of critical physiological processes, including hemodynamic functions [1,2,3]. This pathway is increasingly recognized as a ‘yin and yang’ in relation to its potential opposing effects on the cardiac function, depending on which subfamily of the CYP enzyme is metabolizing AA When it is transformed by epoxidation, AA generates a number of products known as epoxyeicosatrienoic acids (EETs) that promote vasodilation, angiogenesis, and thrombolysis. It inhibits inflammation, smooth muscle cell migration, and apoptosis, which together lead to a preserved cardiac function [7]

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