Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy

Deanna K Sosnowski; K Lockhart Jamieson; Ahmed M Darwesh; Hao Zhang; Hedieh Keshavarz-Bahaghighat; Robert Valencia; Anissa Viveiros; Matthew L Edin; Darryl C Zeldin; Gavin Y Oudit; John M Seubert

doi:10.3389/fcvm.2022.879209

Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy

Front Cardiovasc Med. 2022 May 19:9:879209. doi: 10.3389/fcvm.2022.879209. eCollection 2022.

Authors

Deanna K Sosnowski¹, K Lockhart Jamieson¹, Ahmed M Darwesh¹, Hao Zhang^{2

3}, Hedieh Keshavarz-Bahaghighat¹, Robert Valencia⁴, Anissa Viveiros^{2

3}, Matthew L Edin⁵, Darryl C Zeldin⁵, Gavin Y Oudit^{2

3}, John M Seubert^{1

3

4}

Affiliations

¹ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
² Department of Medicine, Mazankowski Alberta Heart Institute, Edmonton, AB, Canada.
³ Mazankowski Alberta Heart Institute, Edmonton, AB, Canada.
⁴ Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
⁵ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Durham, NC, United States.

Abstract

Objective: Metabolites derived from N-3 and N-6 polyunsaturated fatty acids (PUFAs) have both beneficial and detrimental effects on the heart. However, contribution of these lipid mediators to dilated cardiomyopathy (DCM)-associated mitochondrial dysfunction remains unknown. This study aimed to characterize DCM-specific alterations in the PUFA metabolome in conjunction with cardiac mitochondrial quality in human explanted heart tissues.

Methods: Left ventricular tissues obtained from non-failing control (NFC) or DCM explanted hearts, were assessed for N-3 and N-6 PUFA metabolite levels using LC-MS/MS. mRNA and protein expression of CYP2J2, CYP2C8 and epoxide hydrolase enzymes involved in N-3 and N-6 PUFA metabolism were quantified. Cardiac mitochondrial quality was assessed by transmission electron microscopy, measurement of respiratory chain complex activities and oxygen consumption (respiratory control ratio, RCR) during ADP-stimulated ATP production.

Results: Formation of cardioprotective CYP-derived lipid mediators, epoxy fatty acids (EpFAs), and their corresponding diols were enhanced in DCM hearts. These findings were corroborated by increased expression of CYP2J2 and CYP2C8 enzymes, as well as microsomal and soluble epoxide hydrolase enzymes, suggesting enhanced metabolic flux and EpFA substrate turnover. DCM hearts demonstrated marked damage to mitochondrial ultrastructure and attenuated mitochondrial function. Incubation of fresh DCM cardiac fibers with the protective EpFA, 19,20-EDP, significantly improved mitochondrial function.

Conclusions: The current study demonstrates that increased expressions of CYP-epoxygenase enzymes and epoxide hydrolases in the DCM heart correspond with enhanced PUFA-derived EpFA turnover. This is accompanied by severe mitochondrial functional impairment which can be rescued by the administration of exogenous EpFAs.

Keywords: CYP450; dilated cardiomyopathy (DCM); eicosanoids; mitochondria; soluble epoxide hydrolase (sEH).