Abstract
Elevated cis-epoxyeicosatrienoic acids (EETs) are known to be cardioprotective during ischemia-reperfusion injury in cardiomyocyte-specific overexpressing cytochrome P450 2J2 (CYP2J2) transgenic (Tr) mice. Using the same Tr mice, we measured changes in cardiac and erythrocyte membranes EETs following myocardial infarction (MI) to determine if they can serve as reporters for cardiac events. Cardiac function was also assessed in Tr vs. wild-type (WT) mice in correlation with EET changes two weeks following MI. Tr mice (N = 25, 16 female, nine male) had significantly higher cardiac cis- and trans-EETs compared to their WT counterparts (N = 25, 18 female, seven male). Total cardiac cis-EETs in Tr mice were positively correlated with total cis-EETs in erythrocyte membrane, but there was no correlation with trans-EETs or in WT mice. Following MI, cis- and trans-EETs were elevated in the erythrocyte membrane and cardiac tissue in Tr mice, accounting for the improved cardiac outcomes observed. Tr mice showed significantly better myocardial remodeling following MI, evidenced by higher % fractional shortening, smaller infarct size, lower reactive oxygen species (ROS) formation, reduced fibrosis and apoptosis, and lower pulmonary edema. A positive correlation between total cardiac cis-EETs and total erythrocyte membrane cis-EETs in a Tr mouse model suggests that erythrocyte cis-EETs may be used as predictive markers for cardiac events. All cis-EET regioisomers displayed similar trends following acute MI; however, the magnitude of change for each regioisomer was markedly different, warranting measurement of each individually.
Highlights
Arachidonic acid (AA) is an ω-6 polyunsaturated fatty acid usually found esterified at the sn-2 position in phospholipid membranes
The only exception is that epoxyeicosatrienoic acids (EETs) extracted from both erythrocyte membranes and cardiac tissue were reconstituted in 50 μL solution containing 50% water and 50% of 80:20 acetonitrile:methanol prior to mass spectrometric (MS) analysis
A major goal of this study was to determine if EETs are altered in cardiac tissue during acute injuryAand if this change be captured in circulating levels
Summary
Arachidonic acid (AA) is an ω-6 polyunsaturated fatty acid usually found esterified at the sn-2 position in phospholipid membranes. Another study in humans showed a strong correlation (r = 95%) between plasma and erythrocyte membrane levels of EETs [17] These published data suggest that EETs in erythrocyte membrane, or plasma, can potentially be used to report on EET levels in heart tissue, especially prior to a cardiac event, there are no current studies to validate this correlation between erythrocyte membrane and cardiac EETs. Cardiomyocyte-specific cytochrome P450 2J2 (CYP2J2) is the only CYP2J subfamily member expressed in humans [18]. We assess the potential use of erythrocyte membrane EETs as surrogate markers for cardiac events in a Tr mouse model with cardiomyocyte-specific overexpression of human CYP2J2. The CYP2J2 Tr mice are more suitable to model human cardiac and erythrocyte membrane EET levels, given that the WT mice express several Cyp2j isoforms that are not all epoxygenases. CYP2J2 overexpression is associated with increased EET levels in both cardiac tissue and erythrocyte membranes
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