Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation
CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to <i>cis</i>-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by <i>EPHX2</i>) or re-esterified back to the mem...
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12433 |
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| author | Theresa Aliwarga Jean C. Dinh Scott Heyward Bhagwat Prasad Sina A. Gharib Rozenn N. Lemaitre Nona Sotoodehnia Rheem A. Totah |
| author_facet | Theresa Aliwarga Jean C. Dinh Scott Heyward Bhagwat Prasad Sina A. Gharib Rozenn N. Lemaitre Nona Sotoodehnia Rheem A. Totah |
| author_sort | Theresa Aliwarga |
| collection | DOAJ |
| description | CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to <i>cis</i>-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by <i>EPHX2</i>) or re-esterified back to the membrane. EETs have several cardioprotective properties and higher levels are usually associated with better cardiac outcomes/prognosis. This study investigates how cardiovascular disease (CVD) can influence total EET levels by altering protein expression and activity of enzymes involved in their biosynthesis and degradation. Diseased ventricular cardiac tissues were collected from patients receiving Left Ventricular Assist Device (LVAD) or heart transplants and compared to ventricular tissue from controls free of CVD. EETs, and enzymes involved in EETs biosynthesis and degradation, were measured using mass spectrometric assays. Terfenadine hydroxylation was used to probe CYP2J2 activity. Significantly higher <i>cis</i>- and <i>trans</i>-EET levels were observed in control cardiac tissue (<i>n</i> = 17) relative to diseased tissue (<i>n</i> = 24). Control cardiac tissue had higher CYP2J2 protein levels, which resulted in higher rate of terfenadine hydroxylation, compared to diseased cardiac tissues. In addition, levels of both NADPH-Cytochrome P450 oxidoreductase (POR) and sEH proteins were significantly higher in control versus diseased cardiac tissue. Overall, alterations in protein and activity of enzymes involved in the biosynthesis and degradation of EETs provide a mechanistic understanding for decreased EET levels in diseased tissues. |
| first_indexed | 2024-03-09T20:06:01Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:06:01Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a48cbf9525a046139bd97ff4f7e03b832023-11-24T00:31:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201243310.3390/ijms232012433Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and DegradationTheresa Aliwarga0Jean C. Dinh1Scott Heyward2Bhagwat Prasad3Sina A. Gharib4Rozenn N. Lemaitre5Nona Sotoodehnia6Rheem A. Totah7Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USACertara/SimCYP Ltd., Sheffield S1 2BJ, UKBioIVT, Baltimore, MD 21227, USADepartment of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USAComputational Medicinal Core, Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USACardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USACardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USADepartment of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USACYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to <i>cis</i>-epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by <i>EPHX2</i>) or re-esterified back to the membrane. EETs have several cardioprotective properties and higher levels are usually associated with better cardiac outcomes/prognosis. This study investigates how cardiovascular disease (CVD) can influence total EET levels by altering protein expression and activity of enzymes involved in their biosynthesis and degradation. Diseased ventricular cardiac tissues were collected from patients receiving Left Ventricular Assist Device (LVAD) or heart transplants and compared to ventricular tissue from controls free of CVD. EETs, and enzymes involved in EETs biosynthesis and degradation, were measured using mass spectrometric assays. Terfenadine hydroxylation was used to probe CYP2J2 activity. Significantly higher <i>cis</i>- and <i>trans</i>-EET levels were observed in control cardiac tissue (<i>n</i> = 17) relative to diseased tissue (<i>n</i> = 24). Control cardiac tissue had higher CYP2J2 protein levels, which resulted in higher rate of terfenadine hydroxylation, compared to diseased cardiac tissues. In addition, levels of both NADPH-Cytochrome P450 oxidoreductase (POR) and sEH proteins were significantly higher in control versus diseased cardiac tissue. Overall, alterations in protein and activity of enzymes involved in the biosynthesis and degradation of EETs provide a mechanistic understanding for decreased EET levels in diseased tissues.https://www.mdpi.com/1422-0067/23/20/12433EETs<i>cis</i>-EET<i>trans</i>-EETCYP2J2Cytochrome P450POR |
| spellingShingle | Theresa Aliwarga Jean C. Dinh Scott Heyward Bhagwat Prasad Sina A. Gharib Rozenn N. Lemaitre Nona Sotoodehnia Rheem A. Totah Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation International Journal of Molecular Sciences EETs <i>cis</i>-EET <i>trans</i>-EET CYP2J2 Cytochrome P450 POR |
| title | Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation |
| title_full | Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation |
| title_fullStr | Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation |
| title_full_unstemmed | Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation |
| title_short | Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation |
| title_sort | cardiac disease alters myocardial tissue levels of epoxyeicosatrienoic acids and key proteins involved in their biosynthesis and degradation |
| topic | EETs <i>cis</i>-EET <i>trans</i>-EET CYP2J2 Cytochrome P450 POR |
| url | https://www.mdpi.com/1422-0067/23/20/12433 |
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